Isothiazole derivatives useful as anticancer agents

ABSTRACT

The present invention relates to compounds of the formula 1and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein X1, R1, R2 and R3 are as defined herein. The invention also relates to pharmaceutical compositions containing the above compounds and to methods treating hyperproliferative disorders in mammals by administering the above compounds.

This application claims the benefit of U.S. Provisional Application60/087,963 filed Jun. 4, 1998.

BACKGROUND OF THE INVENTION

This invention relates to novel isothiazole derivatives that are usefulin the treatment of hyperproliferative diseases, such as cancers, inmammals. This invention also relates to a method of using such compoundsin the treatment of hyperproliferative diseases in mammals, especiallyhumans, and to pharmaceutical compositions containing such compounds.

It is known that a cell may become cancerous by virtue of thetransformation of a portion of its DNA into an oncogene (i.e. a genethat upon activation leads to the formation of malignant tumor cells).Many oncogenes encode proteins which are aberrant tyrosine kinasescapable of causing cell transformation. Alternatively, theoverexpression of a normal proto-oncogenic tyrosine kinase may alsoresult in proliferative disorders, sometimes resulting in a malignantphenotype. It has been shown that certain tyrosine kinases may bemutated or overexpressed in many human cancers such as brain, lung,squamous cell, bladder, gastric, breast, head and neck, oesophageal,gynecological and thyroid cancers. Furthermore, the overexpression of aligand for a tyrosine kinase receptor may result in an increase in theactivation state of the receptor, resulting in proliferation of thetumor cells or endothelial cells. Thus, it is believed that inhibitorsof receptor tyrosine kinases, such as the compounds of the presentinvention, are useful as selective inhibitors of the growth of mammaliancancer cells.

It is known that polypeptide growth factors, such as vascularendothelial growth factor (VEGF) having a high affinity to the humankinase insert-domain-containing receptor (KDR) or the murine fetal liverkinase 1 (FLK-1) receptor, have been associated with the proliferationof endothelial cells and more particularly vasculogenesis andangiogenesis. See PCT international application publication number WO95/21613 (published Aug. 17, 1995). Agents, such as the compounds of thepresent invention, that are capable of binding to or modulating theKDR/FLK-1 receptor may be used to treat disorders related tovasculogenesis or angiogenesis such as diabetes, diabetic retinopathy,hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer.

Isothiazole derivatives useful as herbicides are referred to in U.S.Pat. Nos. 4,059,433 and 4,057,416, both assigned to FMC Corporation.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula 1

and to pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein:

wherein X¹ is O or S;

R¹ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, —C(O)(C₁-C₁₀alkyl), —(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(t)(4-10 membered heterocyclic),—C(O)(CH₂)_(t)(C₆-C₁₀ aryl), or —C(O)(CH₂)_(t)(5-10 memberedheterocyclic), wherein t is an integer from 0 to 5; said alkyl groupoptionally includes 1 or 2 hetero moieties selected from O, S and—N(R⁶)— with the proviso that two O atoms, two S atoms, or an O and Satom are not attached directly to each other; said aryl and heterocyclicR¹ groups are optionally fused to a C₆-C₁₀ aryl group, a C₅-C₈ saturatedcyclic group, or a 5-10 membered heterocyclic group; 1 or 2 carbon atomsin the foregoing heterocyclic moieties are optionally substituted by anoxo (═O) moiety; the —(CH₂)_(t)— moieties of the foregoing R¹ groupsoptionally include a carbon-carbon double or triple bond where t is aninteger from 2 to 5; and the foregoing R¹ groups, except H, areoptionally substituted by 1 to 3 R⁴ groups;

R² is selected from the list of substituents provided in the definitionof R¹, —SO₂(CH₂)_(t)(C₆-C₁₀ aryl), —SO₂(CH₂)_(t)(5-10 memberedheterocyclic), and —OR⁵, t is an integer ranging from 0 to 5, the—(CH₂)_(t)— moieties of the foregoing R² groups optionally include acarbon-carbon double or triple bond where t is an integer from 2 to 5,and the foregoing R² groups are optionally substituted by 1 to 3 R⁴groups;

or R¹ and R² may be taken together with the nitrogen to which each isattached to form a 4-10 membered saturated monocyclic or polycyclic ringor a 5-10 membered heteroaryl ring, wherein said saturated andheteroaryl rings optionally include 1 or 2 heteroatoms selected from O,S and —N(R⁶)— in addition to the nitrogen to which R¹ and R² areattached, said —N(R⁶)— is optionally ═N— or —N═ where R¹ and R² aretaken together as said heteroaryl group, said saturated ring optionallymay be partially unsaturated by including 1 or 2 carbon-carbon doublebonds, and said saturated and heteroaryl rings, including the R⁶ groupof said —N(R⁶)—, are optionally substituted by 1 to 3 R⁴ groups;

R³ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, —(CH₂)_(t)(C₆-C₁₀aryl), or —(CH₂)_(t)(5-10 membered heterocyclic), wherein t is aninteger from 0 to 5; said alkyl group optionally includes 1 or 2 heteromoieties selected from O, S and —N(R⁶)— with the proviso that two Oatoms, two S atoms, or an O and S atom are not attached directly to eachother; said aryl and heterocyclic R³ groups are optionally fused to aC₆-C₁₀ aryl group, a C₅-C₈ saturated cyclic group, or a 5-10 memberedheterocyclic group; 1 or 2 carbon atoms in the foregoing heterocyclicmoieties are optionally substituted by an oxo (═O) moiety; the—(CH₂)_(t)— moieties of the foregoing R³ groups optionally include acarbon-carbon double or triple bond where t is an integer from 2 to 5,and the foregoing R³ groups are optionally substituted by 1 to 5 R⁴groups;

each R⁴ is independently selected from C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,azido, —OR⁵, —C(O)R⁵, —C(O)OR⁵, —NR⁶C(O)OR⁵, —OC(O)R⁵, —NR⁶SO₂R⁵,—SO₂NR⁵R⁶, —NR⁶C(O)R⁵, —C(O)NR⁵R⁶, —NR⁵R⁶, —S(O)_(j)R⁷ wherein j is aninteger ranging from 0 to 2, —SO₃H, —NR⁵(CR⁶R⁷)_(t)OR⁶,—(CH₂)_(t)(C₆-C₁₀ aryl), —SO₂(CH₂)_(t)(C₆-C₁₀ aryl), —S(CH₂)_(t)(C₆-C₁₀aryl), —O(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(t)(5-10 membered heterocyclic),and —(CR⁶R⁷)_(m)OR⁶, wherein m is an integer from 1 to 5 and t is aninteger from 0 to 5; said alkyl group optionally contains 1 or 2 heteromoieties selected from O, S and —N(R⁶)— with the proviso that two Oatoms, two S atoms, or an O and S atom are not attached directly to eachother; said aryl and heterocyclic R⁴ groups are optionally fused to aC₆-C₁₀ aryl group, a C₅-C₈ saturated cyclic group, or a 5-10 memberedheterocyclic group; 1 or 2 carbon atoms in the foregoing heterocyclicmoieties are optionally substituted by an oxo (═O) moiety; and thealkyl, aryl and heterocyclic moieties of the foregoing R⁴ groups areoptionally substituted by 1 to 3 substituents independently selectedfrom halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido,—NR⁶SO₂R⁵, —SO₂NR⁵R⁶, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —NR⁶C(O)R⁵,—C(O)NR⁵R⁶, —NR⁵R⁶, —(CR⁶R⁷)_(m)OR⁶ wherein m is an integer from 1 to 5,—OR⁵ and the substituents listed in the definition of R⁵;

each R⁵ is independently selected from H, C₁-C₁₀ alkyl,—(CH₂)_(t)(C₆-C₁₀ aryl), and —(CH₂)_(t)(5-10 membered heterocyclic),wherein t is an integer from 0 to 5; said alkyl group optionallyincludes 1 or 2 hetero moieties selected from O, S and —N(R⁶)— with theproviso that two O atoms, two S atoms, or an O and S atom are notattached directly to each other; said aryl and heterocyclic R⁵ groupsare optionally fused to a C₆-C₁₀ aryl group, a C₅-C₈ saturated cyclicgroup, or a 5-10 membered heterocyclic group; and the foregoing R⁵subsituents, except H, are optionally substituted by 1 to 3 substituentsindependently selected from halo, cyano, nitro, trifluoromethyl,trifluoromethoxy, azido, —C(O)R⁶, —C(O)OR⁶, —CO(O)R⁶, —NR⁶C(O)R⁷,—C(O)NR⁶R⁷, —NR⁶R⁷, hydroxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy; and,

each R⁶ and R⁷ is independently H or C₁-C₆ alkyl;

with the proviso that said compound of formula 1 is not1-methyl-3-(4-carbamoyl-3-ethoxy-5-isothiazolyl)urea,1,1-dimethyl-3-(4-carbamoyl-3-ethoxy-5-isothiazolyl)urea,1-methyl-3-(4-carbamoyl-3-propoxy-5-isothiazolyl)urea,1-methyl-3-(4-carbamoyl-3-(methylthio)-5-isothiazolyl)urea,1-methyl-3-(4-carbamoyl-3-(ethylthio)-5-isothiazolyl)urea,1,1-dimethyl-3-(4-carbamoyl-3-(ethylthio)-5-isothiazolyl)urea,1-methyl-3-(4-carbamoyl-3-(propylthio)-5-isothiazolyl)urea,1,1-dimethyl-3-(4-carbamoyl-3-(propylthio)-5-isothiazolyl)urea, or1-methyl-3-(4-carbamoyl-3-(isopropylthio)-5-isothiazolyl)urea.

Preferred compounds include those of formula 1 wherein R² is H and R¹ isC₁-C₁₀ alkyl optionally substituted by 1 or 2 substituents independentlyselected from —NR⁵R⁶, —NR⁵(CR⁶R⁷)_(t)OR⁶ and —(CH₂)_(t)(5-10 memberedheterocyclic) wherein t is an integer from 0 to 5. Specific preferred R¹groups include propyl, butyl, pentyl and hexyl optionally substituted bydimethylamino, hydroxy, pyrrolidinyl, morpholino, andethyl-(2-hydroxy-ethyl)-amino.

Other preferred compounds include those of formula 1 wherein R² is H andR¹ is —(CH₂)_(t)(5-10 membered heterocyclic), wherein t is an integerfrom 0 to 5; said heterocyclic group is optionally fused to a C₆-C₁₀aryl group, a C₅-C₈ saturated cyclic group, or a 5-10 memberedheterocyclic group; and said R¹ group, including the optionally fusedportions of said R¹ group, is optionally substituted by 1 or 2substituents independently selected from C₁-C₄ alkyl, hydroxy andhydroxymethyl. Specific preferred heterocyclic groups of said R¹ groupare morpholino, pyrrolidinyl, imidazolyl, piperazinyl, piperidinyl, and2,5-diaza-bicyclo[2.2.1]hept-2-yl, the t variable of said R¹ groupranges from 2 to 5, and said heterocyclic groups are optionallysubstituted by hydroxy, hydroxymethyl and methyl.

Other preferred compounds include those of formula 1 wherein R³ is—(CH₂)_(t)(C₆-C₁₀ aryl) wherein t is an integer from 1 to 3 and said R³group is optionally substituted by 1 to 4 R⁴ groups. Specific preferredR³ groups include benzyl optionally substituted by 1 to 4 substituentsindependently selected from halo and C₁-C₄ alkyl. More specificpreferred R³ groups include benzyl substituted by 1 to 4 substituentsindependently selected from methyl, fluoro, chloro and bromo.

Specific embodiments of the present invention include the followingcompounds:

5-{3-[3-(4-Methyl-piperazin-1-yl)-propyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl)-pentyl)-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl]-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido}-isothiazole-4-carboxylicacid amide;

mesylate salt of3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(5-hydroxy-6-piperidin-1-yl)-hexyl)-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

hydrochloride salt of3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(4-Pyrrolidin-1-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[3-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-{3-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Dimethylamino-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Dimethylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Hydroxy-5-isopropropylamino-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-isopropylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(4-Methyl-piperazin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Pyrrolidin-1-yl-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Hydroxy-5-piperidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-(2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxmethyl-piperidin-1-yl)-butyl]-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,6-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-dimethylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-difluoro-benzyloxy)-5-(3-{3-[ethyl-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-(3-{3-[ethyl-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Methylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Amino-propyl)-3-methyl-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Diethylamino-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Chloro-2,6-difluoro-4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

and the pharmaceutically acceptable salts and hydrates of the foregoingcompounds.

The invention also relates to a pharmaceutical composition for thetreatment of a hyperproliferative disorder in a mammal which comprises atherapeutically effective amount of a compound of formula 1, or apharmaceutically acceptable salt or hydrate thereof, and apharmaceutically acceptable carrier. In one embodiment, saidpharmaceutical composition is for the treatment of cancer such as brain,lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck,renal, prostate, colorectal, oesophageal, gynecological (such asovarian) or thyroid cancer. In another embodiment, said pharmaceuticalcomposition is for the treatment of a non-cancerous hyperproliferativedisorder such as benign hyperplasia of the skin (e.g., psoriasis) orprostate (e.g., benign prostatic hypertropy (BPH)).

The invention also relates to a pharmaceutical composition for thetreatment of pancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) in a mammal whichcomprises a therapeutically effective amount of a compound of formula 1,or a pharmaceutically acceptable salt or hydrate thereof, and apharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for theprevention of blastocyte implantation in a mammal which comprises atherapeutically effective amount of a compound of formula 1, or apharmaceutically acceptable salt or hydrate thereof, and apharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for treatinga disease related to vasculogenesis or angiogenesis in a mammal whichcomprises a therapeutically effective amount of a compound of formula 1,or a pharmaceutically acceptable salt or hydrate thereof, and apharmaceutically acceptable carrier. In one embodiment, saidpharmaceutical composition is for treating a disease selected from thegroup consisting of tumor angiogenesis, chronic inflammatory diseasesuch as rheumatoid arthritis, atherosclerosis, skin diseases such aspsoriasis, excema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal which comprises administering to said mammal atherapeutically effective amount of the compound of formula 1, or apharmaceutically acceptable salt or hydrate thereof. In one embodiment,said method relates to the treatment of cancer such as brain, squamouscell, bladder, gastric, pancreatic, breast, head, neck, oesophageal,prostate, colorectal, lung, renal, gynecological (such as ovarian) orthyroid cancer. In another embodiment, said method relates to thetreatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e.g., psoriasis) or prostate (e.g., benignprostatic hypertropy (BPH)).

The invention also relates to a method for the treatment of ahyperproliferative disorder in a mammal which comprises administering tosaid mammal a therapeutically effective amount of a compound of formula1, or a pharmaceutically acceptable salt or hydrate thereof, incombination with an anti-tumor agent selected from the group consistingof mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, and anti-androgens.

The invention also relates to a method of treating pancreatitis orkidney disease in a mammal which comprises administering to said mammala therapeutically effective amount of a compound of formula 1, or apharmaceutically acceptable salt or hydrate thereof.

The invention also relates to a method of preventing blastocyteimplantation in a mammal which comprises administering to said mammal atherapeutically effective amount of a compound of formula 1, or apharmaceutically acceptable salt or hydrate thereof.

The invention also relates to a method of treating diseases related tovasculogenesis or angiogenesis in a mammal which comprises administeringto said mammal an effective amount of a compound of formula 1, or apharmaceutically acceptable salt or hydrate thereof. In one embodiment,said method is for treating a disease selected from the group consistingof tumor angiogenesis, chronic inflammatory disease such as rheumatoidarthritis, atherosclerosis, skin diseases such as psoriasis, excema, andscleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity,macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

Further the compounds of the present invention may be used ascontraceptives in mammals.

Patients that can be treated with the compounds of formulas 1, and thepharmaceutically acceptable salts and hydrates of said compounds,according to the methods of this invention include, for example,patients that have been diagnosed as having psoriasis, BPH, lung cancer,bone cancer, pancreatic cancer, skin cancer, cancer of the head andneck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer or cancer of the anal region, stomach cancer, coloncancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas,carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina or carcinoma of thevulva), Hodgkin's disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system (e.g., cancer of the thyroid,parathyroid or adrenal glands), sarcomas of soft tissues, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, solid tumors of childhood, lymphocytic lymphonas, cancer ofthe bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma,carcinoma of the renal pelvis), or neoplasms of the central nervoussystem (e.g., primary CNS lymphoma, spinal axis tumors, brain stemgliomas or pituitary adenomas).

The present invention also relates to intermediates selected from thegroup consisting of (2,6-difluoro-4-methyl-phenyl)-methanol,(2,3,6-trifluoro-4-methyl-phenyl)-methanol,(4-bromo-2,6-difluoro-phenyl)-methanol,(4-bromo-2,3,6-trifluoro-phenyl)-methanol,(4-chloro-2,6-difluoro-phenyl)-methanol,(3-chloro-2,6-difluoro-phenyl)-methanol, and(4-chloro-2,3,6-trifluoro-phenyl)-methanol.

The present invention also relates to an intermediate selected from thegroup consisting of:

The present invention also relates to an intermediate selected from thegroup consisting of:

wherein R³ is as defined above.

The present invention also relates to a method of preparing a compoundof formula 1 which comprises either

(a) treating a compound of formula 18

with a compound of the formula R³—X wherein X is a halo group and R³ isas defined above, and treating the resulting compound with a compound ofthe formula R¹R²NH wherein R¹ and R² are as defined above; or,

(b) treating a compound of the formula 25

wherein R³ is as defined above, with a compound of the formula R¹R²NHwherein R¹ and R² are as defined above.

The term “halo”, as used herein, unless otherwise indicated, includesfluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloroand bromo.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, cyclic orbranched moieties. It is understood that for cyclic moieties at leastthree carbon atoms are required in said alkyl group.

The term “alkenyl”, as used herein, unless otherwise indicated, includesmonovalent hydrocarbon radicals having at least one carbon-carbon doublebond and also having straight, cyclic or branched moieties as providedabove in the definition of “alkyl”.

The term “alkynyl”, as used herein, unless otherwise indicated, includesmonovalent hydrocarbon radicals having at least one carbon-carbon triplebond and also having straight, cyclic or branched moieties as providedabove in the definition of “alkyl”.

The term “alkoxy”, as used herein, unless otherwise indicated, includesO-alkyl groups wherein “alkyl” is as defined above.

The term “aryl”, as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl.

The term “4-10 membered heterocyclic”, as used herein, unless otherwiseindicated, includes aromatic and non-aromatic heterocyclic groupscontaining one or more heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4-10 atoms in its ring system.Non-aromatic heterocyclic groups include groups having only 4 atoms intheir ring system, but aromatic heterocyclic groups must have at least 5atoms in their ring system. An example of a 4 membered heterocyclicgroup is azetidinyl (derived from azetidine). An example of a 5 memberedheterocyclic group is thiazolyl and an example of a 10 memberedheterocyclic group is quinolinyl. Examples of non-aromatic heterocyclicgroups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the compoundslisted above, may be C-attached or N-attached where such is possible.For instance, a group derived from pyrrole may be pyrrol-1-yl(N-attached) or pyrrol-3-yl (C-attached).

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups which maybe present in the compounds of formula 1. The compounds of formula 1that are basic in nature are capable of forming a wide variety of saltswith various inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds of formula 1 are those that form non-toxic acid additionsalts, i.e., salts containing pharmacologically acceptable anions, suchas the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate,salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate,ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula 1 that are acidic in nature, are capableof forming base salts with various pharmacologically acceptable cations.Examples of such salts include the alkali metal or alkaline earth metalsalts and particularly, the sodium and potassium salts.

Certain compounds of formula 1 may have asymmetric centers and thereforeexist in different enantiomeric forms. This invention relates to the useof all optical isomers and stereoisomers of the compounds of formula 1and mixtures thereof. The compounds of formula 1 may also exist astautomers. This invention relates to the use of all such tautomers andmixtures thereof.

The subject invention also includes isotopically-labelled compounds, andthe pharmaceutically acceptable salts thereof, which are identical tothose recited in formula 1, but for the fact that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S,¹⁸F, and ³⁶Cl, respectively. Compounds of the present invention,prodrugs thereof, and pharmaceutically acceptable salts of saidcompounds or of said prodrugs which contain the aforementioned isotopesand/or other isotopes of other atoms are within the scope of thisinvention. Certain isotopically-labelled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴Cisotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of formula 1 of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

This invention also encompasses pharmaceutical compositions containingand methods of treating bacterial infections through administeringprodrugs of compounds of the formula 1. Compounds of formula 1 havingfree amino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of compounds of formula 1. Theamino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols andalso includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. The amideand ester moieties may incorporate groups including but not limited toether, amine and carboxylic acid functionalities. Free hydroxy groupsmay be derivatized using groups including but not limited tohemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in D. Fleisher, R. Bong, B.H. Stewart, Advanced Drug Delivery Reviews (1996) 19, 115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs and sulfate esters of hydroxy groups. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acylgroup may be an alkyl ester, optionally substituted with groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, are also encompassed. Prodrugs of this type aredescribed in R. P. Robinson et al., J. Medicinal Chemistry (1996) 39,10.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the formula 1 and their pharmaceutically acceptable saltsand solvates may be prepared as described below. Unless otherwiseindicated, R¹, R² and R³ are as defined above.

The compounds of the present invention are readily prepared by followingthe procedures outlined in the schemes illustrated above and typicalsynthetic procedures familiar to those skilled in the art. Scheme 1illustrates the condensation of malononitrile with an isocyanate,oxidation with sulfur, alkylation with an R³ containing compound, andhydration of the nitrile to provide the final compound. In step 1 ofScheme 1, the compound of formula 4 may be prepared by treating thecompound of formula 3 and the compound of formula 2 (R¹ and R² are not Hbut otherwise are as defined above) with a suitably strong base, such asan alkoxide base, preferably sodium ethoxide, in a protic solvent, suchas an alcohol, preferably ethanol, at a temperature ranging from −20° C.to 50° C., preferably 0° C. to 25° C., over a period of about 12 to 24hours. In step 2 of Scheme 1, the compound of formula 5 may be preparedby treating the compound of formula 4 with sulfur (about 1 equivalent toexcess) in a polar solvent, such as an alcoholic solvent, preferablymethanol, at a temperature ranging from 25° C. to 80° C., preferablyabout 65° C., for a period of about 12 to 48 hours, preferably about 24hours. In step 3 of Scheme 1, the compound of formula 6 may be preparedby treating the compound of formula 5 with an R³-containingelectrophile, such as a halide, preferably a chloride, bromide or iodideof such compound, in a polar solvent, preferably tetrahydrofuran (THF)or N,N-dimethylformamide (DMF), using about 1 to 5 equivalent,preferably a bit over 1 equivalent, and a base, such as a tertiary aminebase, preferably diisopropylethylamine, for a period of about 12 to 48hours, preferably about 24 hours, at a temperature ranging from 0° C. to80° C., preferably about 25° C. In step 4 of Scheme 1, the compound offormula 1 (wherein X¹ is S) may be prepared by treating the compound offormula 6 under strongly acidic conditions, such as concentratedsulfuric acid, for a period of about 1 to 12 hours, preferably about 1.5hours, at a temperature ranging from 25° C. to 100° C., preferably about25° C., or under basic conditions, such as with aqueous sodium hydroxide(10%), for a period ranging from 6 to 24 hours at a temperature rangingfrom 25° C. to 120° C., preferably about 100° C.

Scheme 2 illustrates another method of preparing the compounds offormula 1 wherein X¹ is S. In step 1 of Scheme 2, the compound offormula 7 may be prepared by condensation of the compound of formula 3with an alkoxycarbonyl isothiocyanate, such as ethoxy carbonylisothiocyanate, in the presence of a strong base, such as an alkoxidebase, preferably sodium ethoxide, in a polar solvent, such as analcoholic solvent, preferably ethanol, for a period ranging from 12 to24 hours at a temperature ranging from about 0° C. to 30° C. In step 2of Scheme 2, the compound of formula 8 may be prepared by oxidativecyclization of the compound of formula 7 by treating the compound offormula 7 with about 1 equivalent of sulfur in an alcoholic solvent,such as methanol, at a temperature ranging from about 50° C. to 80° C.,preferably about 65° C., for a period ranging from 24 to 48 hours. Instep 3 of Scheme 2, the compound of formula 9 may be prepared bytreating the compound of formula 8 with an R³-containing electrophile,such as a halide, preferably the chloride, bromide or iodide of suchcompound, in a polar solvent, such as THF, at a temperature ranging from25° C. to 40° C. for a period ranging from 12 to 24 hours. In step 4 ofScheme 2, the compound of formula 10 may be prepared by hydrolysing thecompound of formula 9 with a suitably strong acid, such as concentratedsulfuric acid, at a temperature ranging from 80° C. to 120° C. for aperiod of about 6 to 18 hours. In step 5 of Scheme 2, the compound offormula 11 (wherein Ph is phenyl) may be prepared by treating thecompound of formula 10 with an aryl or alkyl chloroformate, such asphenyl chloroformate, and a suitably strong base, such as pyridine, in apolar aprotic solvent, preferably THF or CH₂Cl₂, at a temperatureranging from 25° C. to 40° C. for a period ranging from 12 to 24 hours.In step 6 of Scheme 2, the compound of formula 1 (wherein X¹ is S) maybe prepared by treating the compound of formula 11 with an excess (about1.1 to 6 equivalents) of a primary or secondary amine of the formulaR¹R²NH in a polar aprotic solvent, such as THF or a THF/DMF mixture, ata temperature ranging from 23° C. to 60° C. for a period ranging from 6to 24 hours.

Scheme 3 illustrates a method of preparing the compounds of formula 1wherein X¹ is O. The starting compound of formula 4 may be prepared asdescribed above with reference to Scheme 1. In step 1 of Scheme 3, asolution of the salt of formula 4 in an inert solvent containing wateror, preferably, in water alone, is treated with an oxidizing reagent,preferably dihydrogen peroxide. The mixture is held at a temperature andtime sufficient to effect dissolution and cyclization, preferably atreflux for about 15 minutes, and then cooled to provide the compound offormula 12. In step 2 of Scheme 3, the compound of formula 12 is addedto an acid solution, preferably concentrated sulfuric acid, followed bywater sufficient to effect hydration, preferably about 10 equivalents,and is stirred at a temperature ranging from −20° C. and 100° C.,preferably ambient temperature, for a period to effect hydration,preferably overnight. The mixture is then treated with water or,preferably, ice to provide the compound of formula 13. In step 3 ofScheme 3, the compound of formula 13 is treated with a base, preferablypotassium tert-butoxide, in an inert solvent, preferably DMF, at atemperature ranging from −78° C. to 100° C., preferably ambienttemperature. To this mixture is added an R³ containing electrophile,such as an R³ containing alkyl halide or sulfonate, preferably an iodideor bromide of such compound. The mixture is stirred until the reactionis complete as judged by TLC analysis to provide the compound of formula1 (wherein X¹ is O).

Scheme 4 illustrates another method of preparing the compounds offormula 1 wherein X¹ is S. In step 1 of Scheme 4, the procedure followsthe synthetic procedure outlined in M. Yokoyama and K. Sato, Synthesis,813 (1988). Following this, the compound of formula 3 is treated with analkyl thiol, such as 4-methoxy benzyl mercaptan, and a suitably strongbase, such as sodium hydroxide, in a polar solvent, such as analcohol/water mixture, preferably 1:1 ethanol/water, at a temperatureranging from −10° C. to 30° C., preferably about 0° C., for a periodranging from 2 to 6 hours, preferably about 3 hours, to provide thecompound of formula 14. In step 2 of Scheme 4, the compound of formula15 (Ph is phenyl) may be prepared by treating the compound of formula 14with an alkoxy carbonyl isothiocyanate, such as phenoxy carbonylisothiocyanate, in an aprotic solvent, such as ethyl acetate, at about0° C. for about 12 to 36 hours. In step 3 of Scheme 4, the compound offormula 16 may be prepared by treating the compound of formula 15 withan oxidizing agent, such as bromine or iodine, preferably iodine, and amild base, such as pyridine, in a polar solvent, such as acetonitrile,for about 1 hour at about 0° C. In step 4 of Scheme 4, the compound offormula 17 may be prepared by deprotection of the 4-methoxy benzyl groupby treating the compound of formula 16 with mercuric acetate, about 1equivalent, in the presence of an acid, preferably trifluoroacetic acid(TFA), with an excess of anisole, preferably 10 equivalents, at atemperature ranging from 0° C. to ambient temperature for a periodranging from 10 to 24 hours. In step 5 of Scheme 4, the compound offormula 18 may be prepared by hydration of the compound of formula 17with a suitably strong acid, such as concentrated sulfuric acid, at atemperature ranging from 15° C. to 80° C., preferably ambienttemperature, for a period ranging from 12 to 24 hours, preferably 18hours. In step 6 of Scheme 4, the compound of formula 1 may be preparedby treating the compound of formula 18 with an R³-containingelectrophile, such as a halide, preferably the chloride, bromide oriodide of such compound, and a suitably strong base, such as diisopropylethyl amine, in a polar solvent, preferably DMF, at a temperatureranging from 0° C. to 50° C., preferably 25° C., for a period rangingfrom 12 to 24 hours. The resulting compound is then treated with aprimary or secondary amine of the formula R¹R²NH (about 1.1 to 6equivalents) in a THF/DMF mixture at a temperature ranging from 25° C.to 65° C. for a period ranging from 18 to 36 hours.

Scheme 5 illustrates another method of preparing a compound of formula 1wherein X¹ is O. In step 1 of Scheme 5, a mixture of a thiocyanate salt,preferably potassium thiocyanate, in an inert solvent, preferably ethylacetate, is stirred, preferably vigorously, under an inert atmosphere,overnight to powder the salt. This mixture is then treated with an arylchloroformate of the formula 19 (Ph is phenyl) and the resulting mixtureis stirred at a temperature ranging from −40° C. to ambient temperature,preferably about 5° C., for a period sufficient to effect reaction,preferably about 8 hours. The solid byproduct is filtered off and theproduct is kept cool, preferably not above ambient temperature. Theproduct is redissolved in a suitable inert solvent, preferably ether,and additional insoluble byproduct is removed. After concentration, theproduct is again redissolved in a suitable inert solvent, preferablyhexane, and additional insoluble byproducts removed. The compound offormula 20 is then isolated. In step 2 of Scheme 5, an acidic solution,preferably ethereal HCl, is treated with the compound of formula 3. Upondissolution, the solution is cooled, preferably to 10° C., and istreated with an alcohol, preferably benzyl alcohol. After additionalstirring, the mixture is held at a given temperature, preferably about5° C., for a period sufficient to allow complete reaction, typicallyabout 4 days, to provide the compound of formula 21. In step 3 of Scheme5, a solution of the compound of formula 21 in a suitable inert solvent,preferably acetonitrile, at a temperature ranging from −40° C. toambient temperature, preferably 0° C., is treated with a solution of thecompound of formula 20 in a suitable inert solvent, preferablyacetonitrile. The reaction is kept at a temperature ranging from 0° C.to ambient temperature, preferably ambient temperature, to effectreaction. The mixture is then kept at a temperature appropriate toincrease solidification of the product, preferably about 5° C., forperiod sufficient to maximize yield, preferably about 2 days. Thecompound of formula 22 (Bn is benzyl) is then isolated. In step 4 ofScheme 5, the compound of formula 22 is taken up in a suitable inertsolvent, preferably acetonitrile, at a temperature ranging from −40° C.and 40° C., preferably 0° C., and treated with a base, preferablypyridine, and an oxidant, preferably a solution of bromine or iodine ina suitable inert solvent, preferably acetonitrile. The mixture is thenstirred at a temperature sufficient to effect reaction, preferably at 0°C. for about 1 hour followed by another hour at ambient temperature. Themixture is then allowed to stand at a temperature sufficient to increasesolidification, preferably at 5° C., for a sufficient period, preferablyovernight. The compound of formula 23 is then isolated. In step 5 ofScheme 5, the hydration and deprotection of the compound of formula 23is effected by treatment with an acid, preferably concentrated sulfuricacid. If the compound of formula 23 is sufficiently wet with water fromthe previous step, no additional water is added. If the compound offormula 23 is dry, then additional water is added, preferably about 10equivalents. The reaction is carried out at a temperature ranging from−20° C. to 100° C., preferably ambient temperature, for a periodsufficient to effect complete reaction, typically marked by completedissolution and preferably about 3 hours. After the reaction iscompleted, additional sulfuric acid is added to achieve completeconversion. The mixture is then treated with water or, preferably, ice.The compound of formula 24 is then isolated. In step 6 of Scheme 5, thecompound of formula 24 is combined with a trivalent phosphine,preferably triphenyl phosphine, and an R³ containing alcohol, and istreated with an azodicarboxylate derivative, preferably diisopropylazodicarboxylate, and stirring is continued for a period of at least 1minute. The compound of formula 25 is then isolated. In step 7 of Scheme5, a mixture of the compound of formula 25 in a suitable inert solvent,preferably THF, is treated with a desired amine of the formula R¹R²NHand kept at a temperature sufficient to effect reaction, typically 0° C.to 100° C., preferably 50° C. to 70° C., for a period ranging from 1hour to 48 hours, preferably overnight. The compound of formula 1(wherein X¹ is O) is then isolated.

The compounds of the present invention may have asymmetric carbon atoms.Such diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, for example, bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixtures into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomer mixtures and pureenantiomers are considered as part of the invention.

The compounds of formula 1 that are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate the compound of formula 1 from the reaction mixture asa pharmaceutically unacceptable salt and then simply convert the latterback to the free base compound by treatment with an alkaline reagent andsubsequently convert the latter free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent, such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is readily obtained. The desired acidsalt can also be precipitated from a solution of the free base in anorganic solvent by adding to the solution an appropriate mineral ororganic acid.

Those compounds of formula 1 that are acidic in nature, are capable offorming base salts with various pharmacologically acceptable cations.Examples of such salts include the alkali metal or alkaline-earth metalsalts and particularly, the sodium and potassium salts. These salts areall prepared by conventional techniques. The chemical bases which areused as reagents to prepare the pharmaceutically acceptable base saltsof this invention are those which form non-toxic base salts with theacidic compounds of formulas 1. Such non-toxic base salts include thosederived from such pharmacologically acceptable cations as sodium,potassium, calcium and magnesium, etc. These salts can easily beprepared by treating the corresponding acidic compounds with an aqueoussolution containing the desired pharmacologically acceptable cations,and then evaporating the resulting solution to dryness, preferably underreduced pressure. Alternatively, they may also be prepared by mixinglower alkanolic solutions of the acidic compounds and the desired alkalimetal alkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensurecompleteness of reaction and maximum yields of the desired finalproduct.

Included in the present invention are compounds identical to thecompounds of formula 1 but for the fact that one or more hydrogen orcarbon atoms are replaced by isotopes thereof. Such compounds are usefulas research and diagnostic tools in metabolism pharmokinetic studies andin binding assays. Specific applications in research include radioligandbinding assays, autoradiography studies and in vivo binding studies.Included among the radiolabelled forms of the compounds of formula 1 arethe tritium and C¹⁴ isotopes thereof.

The in vitro activity of the compounds of formula 1 in inhibiting theKDR/VEGF receptor may be determined by the following procedure.

The ability of the compounds of the present invention to inhibittyrosine kinase activity may be measured using a recombinant enzyme inan assay that measures the ability of compounds to inhibit thephosphorylation of the exogenous substrate, polyGluTyr (PGT, Sigma™,4:1). The kinase domain of the human KDR/VEGF receptor (amino acids805-1350) is expressed in Sf9 insect cells as a glutathioneS-transferase (GST)-fusion protein using the baculovirus expressionsystem. The protein is purified from the lysates of these cells usingglutathione agarose affinity columns. The enzyme assay is performed in96-well plates that are coated with the PGT substrate (0.625 μg PGT perwell). Test compounds are diluted in dimethylsulfoxide (DMSO), and thenadded to the PGT plates so that the final concentration of DMSO in theassay is 1.6% (v/v). The recombinant enzyme is diluted inphosphorylation buffer (50 mM Hepes, pH 7.3, 125 mM NaCl, 24 mM MgCl₂).The reaction is initiated by the addition of ATP to a finalconcentration of 10 μM. After a 30 minute incubation at room temperaturewith shaking, the reaction is aspirated, and the plates are washed withwash buffer (PBS-containing 0.1% Tween-20). The amount of phosphorylatedPGT is quantitated by incubation with a HRP-conjugated (HRP ishorseradish peroxidase) PY-54 antibody (Transduction Labs), developedwith TMB peroxidase (TMB is 3,3′,5,5′-tetramethylbenzidine), and thereaction is quantitated on a BioRad™ Microplate reader at 450 nM.Inhibition of the kinase enzymatic activity by the test compound isdetected as a reduced absorbance, and the concentration of the compoundthat is required to inhibit the signal by 50% is reported as the IC₅₀value for the test compound.

To measure the ability of the compounds to inhibit KDR tyrosine kinaseactivity for the full length protein that exists in a cellular context,the porcine aortic endothelial (PAE) cells transfected with the humanKDR (Waltenberger et al., J. Biol. Chem. 269:26988, 1994) may be used.Cells are plated and allowed to attach to 96-well dishes in the samemedia (Ham's F12) with 10% FBS (fetal bovine serum). The cells are thenwashed, re-fed with serum depleted media that contains 0.1% (v/v) bovineserum albumin (BSA), and allowed to incubate for 24 hours. Immediatelyprior to dosing with compound, the cells are re-fed with the serumdepleted media (without BSA). Test compounds, dissolved in DMSO, arediluted into the media (final DMSO concentration 0.5% (v/v)). At the endof a 2 hour incubation, VEGF₁₆₅ (50 ng/ml final) is added to the mediafor an 8 minute incubation. The cells are washed and lysed in HNTGbuffer (20 mM Hepes, pH 7.5, 150 mM NaCl, 0.2% Triton™ X-100, 10%glycerol, 0.2 mM PMSF (phenymethylsulfonyl fluoride), 1 μg/ml pepstatin,1 μg/ml leupeptin, 1 μg/ml aprotonin, 2 mM sodium pyrophosphate, 2 mMsodium orthovanadate). The extent of phosphorylation of KDR is measuredusing an ELISA assay. The 96-well plates are coated with 1 μg per wellof goat anti-rabbit antibody. Unbound antibody is washed off the plateand remaining sites are blocked with Superblock buffer (Pierce) prior toaddition of the anti-flk-1 C-20 antibody (0.5 μg per plate, Santa Cruz).Any unbound antibody is washed off the plates prior to addition of thecell lysate. After a 2 hour incubation of the lysates with the flk-1antibody, the KDR associated phosphotyrosine is quantitated bydevelopment with the HRP-conjugated PY-54 antibody and TMB, as describedabove. The ability of the compounds to inhibit the VEGF-stimulatedautophosphorylation reaction by 50%, relative to VEGF-stimulatedcontrols is reported as the IC₅₀ value for the test compound.

The ability of the compounds to inhibit mitogenesis in human endothelialcells is measured by their ability to inhibit ³H-thymidine incorporationinto HUVE cells (human umbilical vein endothelial cells, Clonetics™).This assay has been well described in the literature (Waltenberger J etal. J. Biol. Chem. 269: 26988, 1994; Cao Y et al. J. Biol. Chem. 271:3154, 1996). Briefly, 10⁴ cells are plated in collagen-coated 24-wellplates and allowed to attach. Cells are re-fed in serum-free media, and24 hours later are treated with various concentrations of compound(prepared in DMSO, final concentration of DMSO in the assay is 0.2%v/v), and 2-30 ng/ml VEGF₁₆₅. During the last 3 hours of the 24 hourcompound treatment, the cells are pulsed with ³H thymidine (NEN, 1 μCiper well). The media are then removed, and the cells washed extensivelywith ice-cold Hank's balanced salt solution, and then 2 times with icecold trichloroacetic acid (10% v/v). The cells are lysed by the additionof 0.2 ml of 0.1 N NaOH, and the lysates transferred into scintillationvials. The wells are then washed with 0.2 ml of 0.1 N HCl, and this washis then transferred to the vials. The extent of ³H thymidineincorporation is measured by scintillation counting. The ability of thecompounds to inhibit incorporation by 50%, relative to control (VEGFtreatment with DMSO vehicle only) is reported as the IC₅₀ value for thetest compound.

The activity of the compounds of formula 1, in vivo, can be determinedby the amount of inhibition of tumor growth by a test compound relativeto a control. The tumor growth inhibitory effects of various compoundsare measured according to the methods of Corbett T. H., et al. “TumorInduction Relationships in Development of Transplantable Cancers of theColon in Mice for Chemotherapy Assays, with a Note on CarcinogenStructure”, Cancer Res., 35, 2434-2439 (1975) and Corbett, T. H., etal., “A Mouse Colon-tumor Model for Experimental Therapy”, CancerChemother. Rep. (Part 2)”, 5, 169-186 (1975), with slight modifications.Tumors are induced in the flank by s.c. injection of 1×10⁶ log phasecultured tumor cells suspended in 0.1-0.2 ml PBS. After sufficient timehas elapsed for the tumors to become palpable (5-6 mm in diameter), thetest animals (athymic mice) are treated with active compound (formulatedby dissolution in appropriate diluent, for example water or 5% Gelucire™44/14 rn PBS by the intraperitoneal (ip) or oral (po) routes ofadministration once or twice daily for 5-10 consecutive days. In orderto determine an anti-tumor effect, the tumor is measured in millimeterswith Vernier calipers across two diameters and the tumor volume (mm³) iscalculated using the formula: Tumor weight=(length×[width]²)/2,according to the methods of Geran, R. I., et al. “Protocols forScreening Chemical Agents and Natural Products Against Animal Tumors andOther Biological Systems”, Third Edition, Cancer Chemother. Rep., 3,1-104 (1972). The flank site of tumor implantation provides reproducibledose/response effects for a variety of chemotherapeutic agents, and themethod of measurement (tumor diameter) is a reliable method forassessing tumor growth rates.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration and the judgement of the prescribing physician.However, an effective dosage is in the range of about 0.001 to about 100mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day,in single or divided doses. For a 70 kg human, this would amount toabout 0.05 to about 7 g/day, preferably about 0.2 to about 2.5 g/day. Insome instances, dosage levels below the lower limit of the aforesaidrange may be more than adequate, while in other cases still larger dosesmay be employed without causing any harmful side effect, provided thatsuch larger doses are first divided into several small doses foradministration throughout the day.

The active compound may be applied as a sole therapy or may involve oneor more other anti-tumour substances, for example those selected from,for example, mitotic inhibitors, for example vinblastine; alkylatingagents, for example cis-platin, carboplatin and cyclophosphamide;anti-metabolites, for example 5-fluorouracil, cytosine arabinoside andhydroxyurea, or, for example, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex™ (tamoxifen) or, for example anti-androgens such as Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefore,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations.

PREPARATION 1 Dimethylcarbamoylisothiocyanate

A three liter, three-neck flask fitted with a mechanical stirrer wascharged with dimethylcarbamyl chloride (250 mL, 2.70 mol) in anhydrousacetonitrile (1.5 L) and heated to reflux. Next was added potassiumthiocyanate (270 g, 2.8 mol, pre-dried at 160° C. under high vacuum for3 hours) portionwise over 1 hour with caution as the reaction bubbledviolently at the start of each addition. After the final addition, themixture was heated at reflux for an additional 1 hour. The heatingmantle was removed and the mixture stirred at ambient temperature for anadditional 2.5 hours and was then stored in the refrigerator overnight.The mixture was filtered to remove unwanted solid material and thefiltrate concentrated. To the resulting oil was added ether (1 L) andthe solid and thick material discarded. The filtrate was againconcentrated affording the desired material a dull orange oil (204 g,1.57 mol, 58%). ¹H NMR (400 MHz, CDCl₃) δ2.90 (s, 3H), 2.98 (s, 3H) ppm.

Sodium, 2,2-dicyano-1-(3.3-dimethyl-ureido)-ethenethiolate

To a 1 M solution of sodium ethoxide in ethanol (prepared by treating110 mL of anhydrous ethanol with 2.5 g (0.11 mole) of sodium) was addedmalononitrile (7.2 g, 0.11 mole) at 0° C.Dimethylcarbamoylisothiocyanate (14.3 g, 0.110 mole) was added, and theresulting mixture was allowed to warm to ambient temperature overnight.The mixture was concentrated in vacuo. The residue was treated withhexanes and was concentrated in vacuo to a solid. The residue wastriturated with hexanes, collected by filtration and dried in vacuoaffording 20 g (83%) of sodium;2,2-dicyano-1-(3,3-dimethyl-ureido)-ethenethiolate as a colorless solid:¹H NMR (400 MHz, DMSO-d₆) δ8.40 (s, 1H), 2.78 (s, 6H) ppm; ¹³C NMR (100MHz, DMSO-d₆): δ189.9, 154.3, 121.4, 118.7, 57.9, 36.5 ppm.

3-(4-Cyano-3-mercagto-isothiazol-5-yl)-1,1-dimethyl-urea

A mixture of sodium, 2,2-dicyano-1-(3,3-dimethyl-ureido)-ethenethiolate(5.0 g, 23 mmol), sulfur (0.734 g, 23 mmol) and 46 mL of methanol wasstirred at reflux for 24 hours. The mixture was filtered, and thefiltrate was concentrated in vacuo. The residue was diluted with waterand the resulting mixture was extracted twice with ethyl acetate. Theaqueous layer was acidified with 1 M HCl (aq) and was extracted intoethyl acetate. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The solid residue was collected and dried in vacuoyielding 2.0 g (40%) of3-(4-cyano-3-mercapto-isothiazol-5-yl)-1,1-dimethyl-urea as a yellowsolid: ¹H NMR (400 MHz, DMSO-d₆) δ2.97 (s, 6H) ppm; MS (APCl, m/z): 227[M-H]⁻

General Procedure for the Alkylation of3-(4-Cyano-3-mercatto-isothiazol-5-yl)-1,1-dimethyl-urea

To a mixture of 3-(4-cyano-3-mercapto-isothiazol-5-yl)-1,1-dimethyl-urea(0.20 g, 0.88 mmol), the appropriate alkyl chloride, alkyl bromide oralkyl iodide (0.90 mmol) and THF or DMF was added diisopropylethylamine(0.116 g, 0.90 mmol). The resulting mixture was stirred for 24 hours atambient temperature. The mixture was partitioned between 1M aqueous HCland ethyl acetate. The organic layer was removed, and the aqueous layerwas extracted three times with ethyl acetate. The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was filtered through a small pad of silica gel eluting withethyl acetate-hexanes (1:1), affording the alkylated product.

3-(4-Cyano-3-hexylsulfanyl-isothiazol-5-yl)-1,1-dimethyl-urea

Following the above general procedure using iodohexane (0.19 g, 0.90mmol) as the alkyl iodide afforded 0.14 g (51%) of3-(4-cyano-3-hexylsulfanyl-isothiazol-5-yl)-1,1-dimethyl-urea as acolorless solid: ¹H NMR (400 MHz, acetone-d₆) δ9.82 (bs, 1H), 3.20 (t,2H, J=7.2 Hz), 3.11 (s, 6H), 1.71 (p, 2H, J=7.2 Hz), 1.43 (m, 2H), 1.31(m, 4H), 0.88 (t, 3H, J=6.0 Hz) ppm; MS (APCl, m/z): 313 [M+H]⁺.

EXAMPLE 15-(3,3-Dimethyl-ureido)-3-hexylsulfanyl-isothiazole-4-carboxylic acidamide

A mixture of3-(4-cyano-3-hexylsulfanyl-isothiazol-5-yl)-1,1-dimethyl-urea (0.09 g,0.29 mmol) and concentrated sulfuric acid (0.18 mL) was stirred atambient temperature for 1.5 hours. The mixture was diluted with icewater, extracted three times into ethyl acetate. The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuoaffording 0.076 g (78%) of5-(3,3-dimethyl-ureido)-3-hexylsulfanyl-isothiazole-4-carboxylic acidamide as a colorless solid: ¹H NMR (300 MHz, acetone-d₆) δ7.08 (bs, 2H),3.20 (t, 2H, J=7.2 Hz), 3.02 (s, 6H), 1.63 (p, 2H, J=7.2 Hz), 1.35 (m,2H), 1.23 (m, 4H), 0.78 (t, 3H, J=6.9 Hz) ppm; MS (APCl, m/z): 331[M+H]⁺.

PREPARATION 2 Sodium. 2,2-dicyano-1-ethoxycarbonylamino-ethenethiolate

Sodium metal (1.01 g, 44 mmol) was dissolved in 40 mL of ethanol atambient temperature. The resulting solution was cooled in an ice bath,and malononitrile (2.91 g, 44 mmol) was added. The ice bath was removed,and the mixture was stirred at ambient temperature for 30 minutes. Aftercooling to 0° C., ethoxycarbonylisothiocyanate (5.77 g, 44 mmol) wasadded, and the mixture was allowed to warm to ambient temperatureovernight. The mixture was concentrated in vacuo, and the residuesolidified upon repeated dilution with hexane and concentration invacuo. The resulting yellow solids were collected and dried in vacuo,affording 10.74 g (100%) of sodium,2,2-dicyano-1-ethoxycarbonylamino-ethenethiolate as a light yellow solidthat containd 0.5 molar equiv. of ethanol as indicated by ¹H NMRspectroscopy. ¹H NMR (300 MHz, DMSO-d₆) δ4.36 (t, 0.5 H, J=5.0 Hz(EtOH)), 4.03 (q, 2H, J=7.1 Hz), 3.43 (dq, 1H J=5.0, 6.7 Hz (EtOH)),1.26 (t, 3H, J=7.3 Hz), 1.06 (t, 1.5H, J=7.0 Hz (EtOH)) ppm; MS (APCl,m/z): 197 [M−Na]⁻.

Sodium, 4-cyano-5-ethoxycarbonylamino-isothiazole-3-thiolate

A mixture of sodium, 2,2-dicyano-1-ethoxycarbonylamino-ethenethiolate(3.3 g, 15 mmol), sulfur (0.48 g, 15 mmol) and methanol (30 mL) washeated at reflux for 24 hours. The mixture was filtered and concentratedin vacuo, and the gummy residue was triturated twice with 10:1ether-ethyl acetate to afford 2.6 g (69%) of sodium,4-cyano-5-ethoxycarbonylamino-isothiazole-3-thiolate as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ3.99 (q, 2H, J=6.8 Hz), 1.16 (t, 3H, J=7.2Hz) ppm; MS (APCI, m/z): 228 [M−Na]⁻.

(4-Cyano-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid ethyl ester

A mixture of sodium,4-cyano-5-ethoxycarbonylamino-isothiazole-3-thiolate (5.0 g, 20 mmol),1-iodopentane (4.0 g, 20 mmol) and tetrahydrofuran (20 mL) was stirredat ambient temperature for 16 hours. After concentration in vacuo, theresidue was partitioned between ethyl acetate and brine. The aqueouslayer was extracted three times with ethyl acetate, and the combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo. The residue was filtered through a pad of silica gel using 1:1ethyl acetate-hexane as eluent. The filtrated was concentrated and theresidue was recrystallized from cold aqueous methanol, affording 2.5 g(42%) (4-cyano-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid ethylester as a colorless solid. An additional 0.5 g (8.4%) was obtained byconcentration of the mother liquor and purification by radialchromatography (4 mm plate, 4:1 hexane-ethyl acetate). ¹H NMR (400 MHz,acetone-d₆) δ11.1 (bs, 1H), 4.32 (q, 2H, J=7.2 Hz), 3.21 (t, 2H, J=7.2Hz), 1.73 (p, 2H, J=6.8 Hz), 1.44-1.28 (m, 7H), 0.90 (t, 3H, J=7.6 Hz)ppm; MS (APCI, m/z): 312 [M+Na]⁺.

5-Amino-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide

A mixture of (4-Cyano-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acidethyl ester (2.7 g, 9.0 mmol) and concentrated sulfuric acid (5 mL) washeated to 100° C. for 6 hours. After cooling to ambient temperature, themixture was diluted with ice water, extracted three times with ethylacetate, and the combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo, affording 2.2 g (100%) of5-amino-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ3.26 (t, 2H, J=7.2 Hz), 1.71 (m, 2H),1.43-1.19 (m, 4H), 0.88 (t, 3H, J=6.8 Hz) ppm.

(4-Carbamoyl-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid phenylester

To a solution of 5-amino-3-pentylsulfanyl-isothiazole-4-carboxylic acidamide (2.2 g, 9.0 mmol) in 36 mL of tetrahydrofuran was added pyridine(0.90 g, 11 mmol) and phenyl chloroformate (1.7 g, 11 mmol). Afterstirring for 3 hours, additional pyridine (0.15 g, 1.9 mmol) and phenylchloroformate (0.29 g, 1.9 mmol) was added, and the mixture was stirredat room temperature overnight. The mixture was concentrated in vacuo,diluted with water and extracted 2× with CH₂Cl₂, 1× with ethyl acetate.The combined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue was triturated for 12hours with ether-hexane, and the resulting solids were collected anddried in vacuo, affording 2.6 g (79%) of(4-carbamoyl-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid phenylester as a colorless solid. ¹H NMR (300 MHz, CDCl₃) δ7.41 (t, 2H, J=7.3Hz), 7.29-7.20 (m, 3H), 3.31 (t, 2H, J=7.3 Hz), 1.72 (m, 2H), 1.50-1.30(m, 4H), 0.90 (t, 3H, J=7.1 Hz) ppm; MS (APCI, m/z): 366 [M+H]⁺.

EXAMPLE 23-Pentylsulfanyl-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide

To a mixture of (4-carbamoyl-3-pentylsulfanyl-isothiazol-5-yl)-carbamicacid phenyl ester (0.10 g, 0.27 mmol) and 1 mL of tetrahydrofuran wasadded N-3-aminopropylpyrollidine (0.175 g, 1.4 mmol). After stirring for72 hours at ambient temperature, the mixture was poured into 1M NaOH,extracted twice with ethyl acetate, and the combined organic layers weredried over Na₂SO₄, filtered and concentrated. Purification of theresidue by radial chromatography (2 mm plate, 3% ethanol-CH₂Cl₂— 30%ethanol-CH₂Cl₂ containing 0.5% NH₄OH), followed by concentration andtrituration of the residue with ether-hexane afforded 0.076 g (78%) of3-pentylsulfanyl-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide as a colorless solid ¹H NMR (400 MHz, CDCl₃) δ7.57 (bs, 1H),7.06 (bs, 2H), 3.35 (m, 2H), 3.26(m, 2H), 2.53 (t, 2H, J=6.8 Hz),2.47(m, 4H), 1.73 (m, 8H), 1.4-1.2 (m, 4H), 0.88 (t, 3H, J=7.2 Hz) ppm;MS (APCI, m/z): 400 [M+H]⁺.

PREPARATION 3 3-(4-Cyano-3-hydroxy-isothiazol-5-yl)-1,1-dimethyl-urea(sodium salt)

A solution of 3-(2,2-Dicyano-1-mercapto-vinyl)-1,1-dimethyl-urea (sodiumsalt) (30 g, 137 mmol) in water (300 mL) was treated at ambienttemperature with hydrogen peroxide (14 mL of a 10 M solution). Thereaction warmed and thickened with solid formation and so was treatedwith additional water (100 mL). The mixture was heated to reflux for 15minutes, effecting complete dissolution and then cooled to ambienttemperature. After 1 hour at ambient temperature, the mixture wasconcentrated to a constant weight (35 g, >100% due to water content) andwas used immediately in the next step.

5-(3,3-Dimethyl-ureido)-3-hydroxy-isothiazole-4-carboxylic acid amide

The solid obtained in the previous step (35 g) was added to concentratedsulfuric acid (150 mL) followed by water (5 mL) and stirred at ambienttemperature overnight. The mixture was treated with ice (500 g) andstirred 2 hours. The mixture was filtered and air pulled through thecake overnight. The solid was crushed with mortar and pestle and keptunder high vacuum until constant weight (21.7 g, 94.2 mmol, 69% over twosteps).

EXAMPLE 3 5-(3,3-Dimethyl-ureido)-3-heptyloxy-isothiazole-4-carboxylicacid amide

A suspension of5-(3,3-Dimethyl-ureido)-3-hydroxy-isothiazole-4-carboxylic acid amide(200 mg, 0.87 mmol) in DMF (5 mL) was treated with KOtBu (107 mg, 0.96mmol) at ambient temperature causing complete dissolution. Next wasadded 1-iodoheptane (1 mL) and the reaction stirred at ambienttemperature until complete dissappearance of starting materials asmeasured by TLC using hexane/ethyl acetate/methanol/acetic acid(48/48/2/2) as eluent. The reaction mixture was then concentrated byrotary evaporation under high vacuum, the residue dissolved in ethylacetate and methanol, and was then purified via radial chromatography (2mm plate) using the same eluent as for TLC affording two components. Themore polar material was identified as the N-alkyated adduct (102 mg,0.311 mmol, 36%). ¹H NMR (400 MHz, CDCl₃) δ0.86 (t, J=6.7 Hz, 3H),1.25-1.31 (m, 8H), 1.64-1.70 (m, 2H), 3.07 (s, 6H), 3.68 (t, J=7.2 Hz,2H), 5.40 (s, 1H), 8.86 (s, 1H), 12.1 (s, 1H) ppm; ¹³C NMR (101 MHz,CDCl₃) δ13.94, 22.45, 26.48, 28.74, 29.52, 31.52, 36.11, 42.54, 166.99ppm; MS (APCI, m/z): 329 [M+H]+. The less polar material was theO-alkyated adduct (134 mg, 0.408 mmol, 48%). ¹H NMR (400 MHz, CDCl₃)δ0.88 (t, J=6.8 Hz, 3H), 1.24-1.50 (m, 8H), 1.75-1.88 (m, 2H), 3.07 (s,6H), 4.43 (t, J=6.7 Hz, 2H), 5.42 (s, 1H), 7.25 (s, 1H appears to besuperimposed on CDCl₃ peak), 11.6 (s, 1H) ppm; ¹³C NMR (101 MHz, CDCl₃ )δ13.94, 22.45, 25.86, 28.83, 31.60, 36.11, 68.69, 97.69, 154.15, 162.27,166.20, 169.45 ppm; MS (APCI, m/z): 329 [M+H]⁺.

PREPARATION 4 2-Cyano-thioacetimidic acid 4-methoxy-benzyl ester

To a solution of sodium hydroxide (13 g, 0.32 mol) in 750 mL of 1:1ethanol-water at 0° C. was added 4-methoxybenzylmercaptan (50 g, 0.324mol) and malononitrile (21 g, 0.324 mol). After stirring for 3 hours at0° C., the mixture was diluted with 500 mL of saturated aqueous NH₄Cl,diluted with 4 l of water and filtered. The solids were washed withether, and the filtrated was diluted with an equal volume of hexane andfiltered. The combined solids were dried in vacuo, affording 43 g (60%)of 2-cyano-thioacetimidic acid 4-methoxy-benzyl ester as a colorlesssolid. ¹H NMR (400 MHz, CDCl₃) δ7.22 (d, 2H, J=7.6 Hz), 6.84 (d, 2H,J=8.8 Hz), 4.74 (bs, 1H), 3.98 (s, 2H), 3.78 (s, 3H) ppm; MS (APCI,m/z): 221 [M+H]⁺.

2-Cyano-3-mercapto-3-phenoxycarbonylamino-thioacrylimidic acid4-methoxy-benzyl ester

To a solution of of 2-cyano-thioacetimidic acid 4-methoxy-benzyl ester(42 g, 0.19 mol) in 191 mL of ethyl acetate at 0° C. was addedphenoxycarbonylisothiocyanate (34 g, 0.19 mol), and the mixture wasstirred at 0° C. for 24 hours. The mixture was diluted with ether andfiltered. The solids were washed with ether, collected and dried invacuo, affording 56 g (73%) of2-cyano-3-mercapto-3-phenoxycarbonylamino-thioacrylimidic acid4-methoxy-benzyl ester as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ12.81(s, 1H), 9.01 (s, 1H), 8.68 (s, 1H) 7.28-6.99 (m, 7H), 6.69 (d,2H, J=8.8 Hz), 4.17 (s, 2H), 3.64 (s, 3H) ppm; MS (APCI, m/z): 400[M+H]⁺.

[4-Cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl]-carbamic acidphenyl ester

To a mixture of2-Cyano-3-mercapto-3-phenoxycarbonylamino-thioacrylimidic acid4-methoxy-benzyl ester (11 g, 28 mmol) and ethyl acetate (250 mL) wasadded, at 0° C., pyridine (4.4 g, 55 mmol). A solution of iodine (7.0 g,28 mmol) in 350 mL of ethyl acetate was added dropwise over 1 hour. Theresulting suspension was stirred for 1 hour, treated with 200 mL of 1 MHCl and filtered, affording 7.0 g (64%) of[4-cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl]-carbamic acidphenyl ester as a colorless solid. The filtrate was extracted with 1 lof ethyl acetate, and the organic phase was washed with aqueous NaHCO₃,dried over Na₂SO₄, filtered and concentrated, yielding an additional 2.8g (26%) of[4-cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl]-carbamic acidphenyl ester. ¹H NMR (400 MHz, CDCl₃) δ11.95 (s, 1H), 7.35 (t, 2H, J=8.4Hz), 7.20 (m, 3H), 7.13 (d, 2H, J=8.0 Hz), 6.78 (t, 2H, J=8.6 Hz), 4.34(s, 2H), 3.73 (s, 3H) ppm; MS (APCI, m/z): 398 [M+H]⁺.

(4-Cyano-3-mercapto-isothiazol-5-yl)-carbamic acid phenyl ester

To a mixture of[4-cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl]-carbamic acidphenyl ester (1.0 g, 2.5 mmol), trifluoracetic acid (26 mL) and anisole(2.7 g, 25 mmol) at 0° C. was added mercuric acetate (0.80 g, 2.5 mmol).The mixture was allowed to warm to room temperature overnight. Afterconcentration in vacuo, the mixture was diluted with 100 mL of water and100 mL of ethyl acetate. Hydrogen sulfide was bubbled in slowly untilprecipitation of the mercury salts was complete. The mixture was dilutedwith brine, extracted 3× with 200 mL of ethyl acetate, and the combinedorganic layers were filtered through celite, dried over Na₂SO₄, filteredand concentrated in vacuo, affording 0.70 g (100%) of(4-cyano-3-mercapto-isothiazol-5-yl)-carbamic acid phenyl ester as acolorless solid. ¹H NMR (400 MHz, acetone-d₆) δ7.47 (t, 2H, J=7.6 Hz),7.35-7.30 (m, 3H) ppm; MS (APCI, m/z): 276 [M−H]⁻.

(4-Carbamoyl-3-mercapto-isothiazol-5-yl)-carbamic acid phenyl ester

A mixture of (4-cyano-3-mercapto-isothiazol-5-yl)-carbamic acid phenylester (0.70 g, 2.5 mmol), 2,6-di-tert-butyl-4-methylphenol (BHT) (onecrystal) and concentrated sulfuric acid (3 mL) was stirred for 18 hoursat room temperature. The mixture was diluted with ice water, extracted3× with ethyl acetate, and the combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was dissolved in10 mL of ethanol at 0° C. and was treated with 0.096 g (2.5 mmol) ofNaBH₄. After stirring for 30 minutes, the mixture was acidified with 1 MHCl, extracted into ethyl acetate, dried over Na₂SO₄, filtered andconcentrated in vacuo, affording 0.60 g (81%) of(4-carbamoyl-3-mercapto-isothiazol-5-yl)-carbamic acid phenyl ester as ayellow solid. ¹H NMR (400 MHz, acetone-d₆) δ13.0 (s, 1H), 11.0-10.9 (bs,1H), 10.3 (s, 1H), 7.47 (t, 2H, J=6.8 Hz), 7.37-7.30 (m, 4H), ppm; MS(APCI, m/z): 296 [M+H]³⁰ .

EXAMPLE 45-[3-(3-Chloro-4-fluoro-benzyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide

To a mixture of (4-carbamoyl-3-mercapto-isothiazol-5-yl)-carbamic acidphenyl ester (0.075 g, 0.25 mmol) in 0.5 mL of DMF was added4-methylbenzylchloride (0.036 g, 0.25 mmol), followed byN,N-diisopropylethylamine (0.033 g, 0.25 mmol). After stirring for 18hours at ambient temperature, tetrahydrofuran (1 mL) was added, followedby 3-chloro-4-fluorobenzylamine (0.081 g, 0.51 mmol). After stirring for24 hours at 45° C., the mixture was diluted with 1M HCl, extracted 3×with ethyl acetate, and the combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byradial chromatography on silica gel eluting with ethyl acetate-hexane,affording 26 mg of5-[3-(3-chloro-4-fluoro-benzyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide as a colorless solid. HPLC ret. time: 4.9 minutes. ¹H NMR(400 MHz, acetone-d₆) δ7.95 (bs, 1H), 7.54 (dd, 1H, J=2, 7.2 Hz), 7.39(m, 1H), 7.31-7.25 (m, 3H), 7.11 (d, 2H, J=8.0 Hz), 7.01 (bs, 2H), 4.48(m, 4H), 2.28 (s, 3H) ppm; MS (APCI, m/z): 465 [M+H]⁺.

PREPARATION 5 2-Cyano-acetimidic acid benzyl ester

To a solution of ethereal HCl (4.00 L, 1M, 4.00 mol) was added warmed(liquified) malononitrile (252 mL, 4.00 mol). Upon dissolution, thesolution was cooled to 10° C. Next was added benzyl alcohol (414 mL,4.00 mol) and the mixture stirred at 10° C. for 0.5 hour. The reactionflask was placed in the refrigerator and allowed to stand at 5° C. for 4days. The solid obtained was filtered cold, washed with cold ether (1.5L) and dried under vacuum (40 mm Hg) for 1 hour affording 545 g (2.59mol, 65%) of the Pinner adduct as a white solid. The neutralization ofthis HCl salt was carried out as follows. A solution of potassiumcarbonate (359 g, 2.59 mol) in water (700 mL) was prepared and cooled to5° C. The solution was added to a separatory funnel along with ether (2L) and THF (500 mL). The entire separatory funnel was placed in an icebath until the temperature of the extractant solution was 5° C. ThePinner adduct (545 g, 2.59 mol) was then added to the separatory funneland the funnel was shaken vigorously for 5 minutes. The aqueous layerwas discarded and the organic layer collected following filtration ofsuspended particles. The organic layer was placed again into theseparatory funnel, shaken with brine and allowed to settle completely toallow virtual complete removal of brine layer. The organic layer wasconcentrated on a rotary evaporator and the unstable product (327 g,1.88 mmol, 73%) used immediately in the next step.

Phenoxycarbonylisothiocyanate

A suspension of KSCN (80 g, 823 mmol, from a fresh, previously unopenedbottle) in ethyl acetate (2 L, dry) was stirred vigorously overnightunder an atmosphere of nitrogen in order to powder the KSCN. The finesuspension was then treated dropwise with phenyl chloroformate (100 mL,800 mmol) over 1 hour. The reaction was stirred overnight at ambienttemperature and then stirred at 5° C. for 8 hours. The KCl produced wasfiltered off and the solvent removed by rotary evaporation taking carenot to warm the product above ambient temperature. The product wasredissolved in ether (2 L), the additional precipitate removed byfiltration and discarded, and the ethereal solution of product againconcentrated under reduced pressure taking care not to warm the productabove ambient temperature. The product was redissolved in hexane (2 L),the additional precipitate removed by filtration and discarded, and thehexane solution of product again concentrated under reduced pressuretaking care not to warm the product above ambient temperature. Theproduct so obtained (101 g, 564 mmol, 68%) was highly pure and could bestored at −5° C. for a matter of several days, or at room temperaturefor a few hours, but was typically used quickly, as in the currentexample. ¹H NMR (400 MHz, CDCl₃) δ7.10-7.21 (m, 2H), 7.21-7.31 (m, 1H),7.31-7.45 (m, 2H) ppm; ¹³C NMR (101 MHz, CDCl₃) δ120.75, 126.77, 129.65,150.46 ppm; IR (neat) 1190, 1232, 1491, 1590, 1751, 1960 cm−1.

2-Cyano-3-mercapto-3-phenoxycarbonylamino-acrylimidic acid benzyl ester

To a stirred 0° C. solution of 2-cyano-acetimidic acid benzyl ester (327g, 1.88 mol) in acetonitrile (1 L) was added a 0° C. solution ofphenoxycarbonylisothiocyanate (353 g, 1.97 mol) in acetonitrile (1 L).The reaction was allowed to warm to ambient temperature and was stirredovernight. The mixture was then placed in the refrigerator and keptstill at 5° C. for 48 hours. The solid product was filtered, compressed,and washed with 20° C. acetonitrile (3×200 mL). Air was then drawnthough the relatively stable solid followed by further drying under highvacuum to yield a yellow solid (282 g, 798 mmol, 42%). ¹H NMR (400 MHz,DMSO) δ5.39 (s, 2H), 7.11-7.19 (m, 2H), 7.20-7.24 (m, 1H), 7.36-7.46 (m,7H), 10.23 (broad s, 1H), 10.67 (s, 1H), 12.19 (broad s, 1H) ppm; MS(APCI, m/z): 354 [M+H]⁺.

(3-Benzyloxy-4-cyano-isothiazol-5-yl)-carbamic acid phenyl ester

To a 0° C. suspension of the adduct,2-cyano-3-mercapto-3-phenoxycarbonylaminoacrylimidic acid benzyl ester(282 g, 798 mmol) in acetonitrile (2 L) was added pyridine (129 mL, 1.60mol). Next was added a solution of bromine (41.1 mL, 798 mmol) inacetonitrile (200 mL) over 15 minutes. The reaction was stirred at 0° C.for an additional 1 hour and then at ambient temperature for 2 hour. Themixture was placed in the refrigerator and held at 5° C. overnight. Thesolid product was filtered and washed with 0° C. ether (1 L), dried inthe same funnel by drawing air through the solid for 4 hours. The solidwas added to water (1 L), stirred vigorously for 1 hour, filtered anddried in the same funnel by drawing air through the solid overnight toafford a white solid (320 g pure though still containing some water)that was used, as is, in the next step. ¹H NMR (400 MHz, DMSO) δ5.35 (s,2H), 7.25-7.45 (m, 10H), 13.20 (broad s, 1H) ppm; MS (APCI, m/z): 350[M−H]⁻.

(4-Carbamoyl-3-hydroxy-isothiazol-5-yl)-carbamic acid phenyl ester

The wet solid, (3-Benzyloxy-4-cyano-isothiazol-5-yl)-carbamic acidphenyl ester, (320 g) was added slowly to concentrated sulfuric acid(650 mL) over 1.5 hours. Additional concentrated sulfuric acid (100 mL)was added and the mixture stirred a further 3 hours. The viscoussolution was diluted by slow addition of ice (2000 g) followed byvigorous stirring for an additional 2 hours. The acid was partiallyremoved by dividing the suspension into eight containers that wereplaced in a centrifuge, spun at 3000 rpm for 45 minutes at 21° C. Theaqueous layer was discarded, additional pure water was added, the pelletresuspended, and the process repeated. After sevendilution/centrifugation/redilution cycles, the pH of the aqueous layerhad increased to ˜4 and the solid was collected and dried by drawing airthrough a cake in a funnel for 2 days. The less-wet solid was crushed,placed again in the filter, and air was again drawn through the solidfor another day. This process was repeated until the solid was dry toafford a tan solid (234 g, 105% over two steps, minor impuritiespresent—did not interfere appreciably with the subsequent steps). ¹H NMR(400 MHz, DMSO) δ7.00 (broad s, 1H), 7.27-7.31 (m, 3H), 7.40-7.45 (m,2H), 7.89 (s, 1H), 8.08 (s, 1H), 11.92 (s, 1H); MS (APCI, m/z): 184[M−(H and PhOH)]⁻.

[4-Carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester

To a suspension of (4-carbamoyl-3-hydroxy-isothiazol-5-yl)carbamic acidphenyl ester (1.77 g, 6.23 mmol), triphenylphosphine (1.99 g, 7.59mmol), o,o′-difluoro-p-methylbenzyl alcohol (1.00 g, 6.32 mmol) in THF(21 mL) was added diisopropyl azodicarboxylate (DIAD, 1.49 mL, 7.59mmol) slightly faster than dropwise. The reaction mixture warmed andbecame clear. After stirring for 15 minutes, the majority of THF wasremoved by rotary evaporation and the crude mixture purified on silicagel using chloroform/acetone/acetic acid (98.5/0.75/0.75) as eluent toafford a white solid (802 mg, 1.91 mmol, 30%).

EXAMPLE 53-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide

To a suspension of[4-Carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester (125 mg, 0.298 mmol) in THF (1 mL) was added1-(3-aminopropyl)-4-methylpiperazine (70 mg, 0.45 mmol). The mixture wasshaken at 50° C. overnight, cooled to ambient temperature, and loadeddirectly onto a radial chromatograph followed by elution withchloroform/methanol/concentrated ammonium hydroxide (50/5/1) to afford awhite solid (121 mg, 0.251 mmol, 84%). ¹H NMR (400 MHz, CDCl₃) δ1.72 (t,J=5.81 Hz, 2H), 2.20-2.85 (m, 10H), 2.28 (s, 3H superimposed onmultiplet from 2.20-2.85), 2.35 (s, 3H superimposed on multiplet from2.20-2.85), 3.39 (t, J=5.4 Hz, 2H), 5.51 (s, 2H), 5.74 (broad s, 1H),6.74 (d, J=8.3 Hz, 2H), 7.05 (s, 1H), 7.58 (broad s, 1H), 11.01 (broads, 1H) ppm; MS (APCI, m/z): 483 [M+H]⁺.

1,3-Difluoro-5-methyl-benzene (G═H)

A mixture of 1-bromomethyl-3,5-difluoro-benzene (75 g, 0.362 mol), Pd/C(5%, 5 g), and sodium acetate (208 g, 2.54 mol) in ether (300 mL) wastreated with hydrogen gas (50 psi) in a Parr shaker for 2 days. Themixture was filtered through Celite and the organic solution washedthree times with saturated aqueous sodium bicarbonate solution. Theaqueous layers were washed with ether and the combined organic layersdried (MgSO₄), filtered, and partially concentrated by evaporation usinga cold water bath. The volatile product was obtained as a mixture withether and the ratio (˜3:2, ether:product, g:g) calculated based on ¹HNMR integration to determine actual yield (45.5 g, 0.355 mol, 98%) ofproduct for scaling reagents in the ensuing reaction. ¹H NMR (400 MHz,CDCl₃) δ2.25 (s, 3H), 6.51-6.56 (m, 1H), 6.58-6.60 (m, 2H) ppm.

1,2,5-Trifluoro-3-methyl-benzene (G═F)

The title compound was prepared from1-bromomethyl-2,3,5-trifluoro-benzene by a procedure analogous to thatfor 3,5-difluorotoluene, above. ¹H NMR (400 MHz, CDCl₃) δ ppm; MS (APCI,m/z): [M+H]+.

(2,6-Difluoro-4-methyl-phenyl)-methanol (G═H, G′═Me, G″═F)

A solution of 1,3-difluoro-5-methyl-benzene (45.5 g, 0.355 mol, mixedwith a small volume of ether) in dry THF (1.77 L) was cooled to −78° C.under nitrogen and treated dropwise with n-BuLi (142 mL of a 2.5 Msolution in hexanes, 0.355 mol). The solution was stirred an additional25 minutes and was then treated with DMF (27.5 mL, 0.355 mol). Afterstirring an additional 45 minutes, the solution was treated with aceticacid (40.6 mL, 0.71 mol) and the flask removed from the −78° C. bath.The mixture was stirred at ambient temperature for 2 hours and was thentreated successively with water (300 mL) and MeOH (300 mL). Next wasadded, portionwise, NaBH₄ (26.8 g, 0.71 mol) followed by stirring for 1hour. The flask was cooled in an ice bath and the mixture treated with 6N HCl until pH˜5. The mixture was concentrated via rotary evaporation toremove THF and MeOH and the product extracted with ether and washedseveral times with small volumes of water and once with brine. The etherlayer was dried (MgSO₄), filtered, and concentrated to afford an oil (45g, 0.285 mol, 80%) that solidified upon refrigeration. ¹H NMR (400 MHz,CDCl₃) δ1.75 (t, J=6.5 Hz, 1H), 2.32 (s, 3H), 4.72 (d, J=6.4 Hz, 2H),6.69 (d, J=7.9 Hz, 2H) ppm.

(2,3,6-Trifluoro-4-methyl-phenyl)-methanol (G═F, G′═Me, G″═F)

The title compound was prepared from 1,2,5-trifluoro-3-methyl-benzene bya procedure analogous to that for(2,6-difluoro-4-methyl-phenyl)-methanol, above. ¹H NMR (400 MHz, CDCl₃)δ1.87 (broad s, 1H), 2.28 (d, J=1.9 Hz, 3H), 4.74 (s, 2H), 6.68-6.72 (m,1H) ppm.

(4-Bromo-2,6-difluoro-phenyl)-methanol (G═H, G′═Br, G″═F)

The title compound was prepared from 1-bromo-3,5-difluoro-benzene by aprocedure analogous to that for (2,6-difluoro-4-methyl-phenyl)-methanol,above with the following exception: lithium diisopropylamide (LDA) wasused in place of n-BuLi and deprotonation time was extended to 45minutes. ¹H NMR (400 MHz, CDCl₃) δ1.91 (t, J=6.5 Hz, 1H), 4.71 (d, J=6.4Hz, 2H), 7.06-7.12 (m, 2H) ppm.

(4-Bromo-2,3,6-trifluoro-phenyl)-methanol (G═F, G′═Br, G″═F)

The title compound was prepared from 1-bromo-2,3,5-trifluoro-benzene bya procedure analogous to that for(2,6-difluoro-4-methyl-phenyl)-methanol, above with the followingexception: lithium diisopropylamide (LDA) was used in place of n-BuLiand deprotonation time was extended to 45 minutes. ¹H NMR (400 MHz,CDCl₃) δ1.89 (t, J=6.5 Hz, 1H), 4.75 (d, J=6.4 Hz, 2H), 7.11-7.15 (m,1H) ppm.

(3-Chloro-2,6-difluoro-phenyl)-methanol (G═Cl, G′═H. G″═F)

The title compound was prepared from 1-chloro-2,4-difluoro-benzene by aprocedure analogous to that for (2,6-difluoro-4-methyl-phenyl)-methanol,above. ¹H NMR (400 MHz, CDCl₃) δ1.90 (t, J=6.4 Hz, 1H), 4.78 (d, J=6.4Hz, 2H), 6.87 (app. dt, J=1.8, 8.9 Hz, 1H), 7.32 (app. dt, J=5.8, 2.8Hz, 1H) ppm.

(2-Fluoro-4,6-dimethyl-phenyl)-methanol (G═H, G′═Me, G″═Me)

A solution of N,N,N′,N′-tetramethylethylenediamine (13.4 mL, 88.6 mmol)in THF (115 mL) was cooled to −78° C. and treated with sec-BuLi (68.2 mLof of 1.3 M solution in cyclohexane, 88.6 mmol). The resulting yellowsolution was stirred for 20 minutes at −78° C. and was then treated witha solution of 1-fluoro-3,5-dimethyl-benzene (10.0 g, 80.5 mmol) in THF(56 mL). The mixture was stirred for 1 hour at −78° C. and was thentreated with a solution of DMF (6.86 mL, 88.6 mmol) in THF (26 mL). Thereddish-brown mixture was stirred an additional 1 hour, and was thentreated with HOAc (10 mL) and water (200 mL). The mixture was warmed toambient temperature, extracted with ether (500 mL) and the aqueous layerextracted with additional ether (2×300 mL). The combined organicextracts were combined and washed successively with 0.2 M HCl (2×200mL), water (500 mL) and brine (300 mL). The organic layer was dried(MgSO₄) and concentrated to afford the aldehyde as a clear oil (11.9 g,78.2 mmol, 97%). The aldehyde was then dissolved in THF (100 mL), MeOH(100 mL), and water (100 mL) and treated portionwise with NaBH₄ (2.96 g,78.2 mmol). The mixture was stirred at ambient temperature for 1 hourand was then concentrated under reduced pressure to remove the THF andMeOH. The remaining aqueous layer was extracted twice with ether (600 mLand 200 mL) and the combined organic layers washed successively with 0.1M HCl (300 mL), water (300 mL), and brine (300 mL). The organic layerwas dried (MgSO₄) and concentrated to afford an oil (10.8 g, 70.4 mmol,90%). ¹H NMR (400 MHz, CDCl₃) δ2.28 (s, 3H), 2.38 (s, 3H), 4.70 (s, 2H),6.71 (d, J=10.6 Hz, 1H), 6.79 (s, 1H) ppm.

(2-Fluoro-4-methyl-phenyl)-methanol (G═H, G′═Me, G″═H)

A solution of 4-bromo-3-fluorotoluene (12.2 g, 64.7 mmol) in THF (170mL) was cooled to −78° C. and treated dropwise with n-BuLi (25.9 mL of a2.5 M solution in hexanes, 65 mmol). After stirring for 1 hour, thesolution was treated with N,N-dimethylformamide (DMF) (5.5 mL, 71 mmol)and stirred an additional 30 minutes followed by addition of acetic acid(12 mL). The flask was removed from the cold-bath and allowed to warm toambient temperature. Next was added water and the product extracted withether. The organic layer was washed successively with dilute HCl andbrine and was then dried (MgSO₄) and concentrated. The procedure wasrepeated (using 11.8 g 4-bromo-3-fluorotoluene) and the combinedmaterial subjected to the following reduction: The aldehyde (17.6 g, 127mmol) was dissolved in THF (165 mL), MeOH (165 mL), and water (165 mL).Next was added NaBH₄ (5.3 g, 140 mmol) portionwise over several minutes(bubbling, exothermic) and stirring was continued for 2 hours. Thereaction was diluted with a large volume of ether and was treated withdilute HCl to quench. The layers were separated and the organic layerwas dried (MgSO₄) and concentrated to afford the product as an oil (17.0g, 121 mmol, 95%). ¹H NMR (400 MHz, CDCl₃) δ2.33 (s, 3H), 4.69 (s, 2H),6.86 (d, J=11.2 Hz, 1H), 6.93 (d, J=7.9 Hz, 1H), 7.24-7.28 (m, 1H) ppm.

(4-Chloro-2,5-difluoro-phenyl)-methanol

To a mixture of 4-chloro-2,5-difluoro-benzoic acid (15 g, 78 mmol)tetrahydrofuran (THF) (75 mL) and trimethylborate (26 mL, 230 mmol) wasadded borane-methylsulfide complex (86 mL, 86 mmol, 10 M solution inDMS), and the mixture was stirred for 18 hours at ambient temperature.Additional borane-methylsulfide complex (2.47 mL, 24.7 mmol) was addedto drive the reaction to completion. The mixture was poured into 1Maqueous NaOH, extracted 3× with ether, and the combined organic layerswere dried over anhydrous MgSO₄, filtered and concentrated in vacuo.Trituration of the solid residue with ether-hexane afforded 14 g of(4-chloro-2,5-difluoro-phenyl)-methanol as a colorless solid. ¹H NMR(400 MHz, CDCl₃) δ7.26 (dd, 1H, J=6, 8.8 Hz), 7.11 (dd, 1H, J=6, 9.2Hz), 4.71 (d, 2H, J=6.0 Hz), 1.80 (t, 1H, J=6.0 Hz) ppm.

tert-Butyl-(2,3-difluoro-benzyloxy)-dimethyl-silane

To a solution of (2,3-difluoro-phenyl)-methanol (5.0 g, 35 mmol),imidazole (4.9 g, 72 mmol) and DMF (40 mL) was addedtert-butyldimethylchlorosilane (5.4 g, 36 mmol). After stirring atambient temperature for 24 hours, the mixture was partitioned between400 mL of ether and 100 mL of water. The organic layer was washed twicewith water, dried over MgSO₄, filtered and concentrated in vacuo,affording 6.8 g of tert-butyl-(2,3-difluoro-benzyloxy)-dimethyl-silaneas a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.22 (m, 1H), 7.04 (m, 2H),4.79 (s, 2H), 0.91 (s, 9H), 0.12 (s, 6H) ppm.

tert-Butyl-(2,3-difluoro-4-methyl-benzyloxy)-dimethyl-silane

To a solution of TMEDA (3.9 mL, 3.0 g, 26 mmol) in THF (33 mL) at −78°C. was added sec butyllithium (20 mL, 1.3 M in hexane, 26 mmol). Afterstirring for 20 minutes, a solution oftert-butyl-(2,3-difluoro-benzyloxy)-dimethyl-silane (6.0 g, 23 mmol) in17 mL of THF was added dropwise. After stirring for 1 hour, the solutionwas added dropwise to a solution of methyl iodide (8 mL) in THF (40 mL)at −20° C. After stirring for 18 hours, the mixture was quenched withsaturated aqueous NH₄Cl, extracted 3× into ether, and the combinedorganic layers were dried over MgSO₄, filtered and concentrated invacuo, giving 6.6 g oftert-butyl-(2,3-difluoro-4-methyl-benzyloxy)-dimethyl-silane as a lightyellow oil. ¹H NMR (400 MHz, CDCl₃) δ7.07 (app. t, 1H, J=7.2 Hz), 6.89(app. t, 1H, J=7.3 Hz), 4.74 (s, 2H), 2.26 (d, 3H, J=1.9 Hz), 0.87 (s,9H), 0.07 (s, 6H) ppm.

(2,3-Difluoro-4-methyl-phenyl)-methanol

To a solution oftert-butyl-(2,3-difluoro-4-methyl-benzyloxy)-dimethyl-silane (6.5 g, 24mmol) in THF (24 mL) was added tetrabutylammonium fluoride (24 mL of a1M solution in THF, 24 mmol). After stirring at ambient temperature for1 hour, the mixture was poured into water, acidified with 1M aqueousHCl, extracted 3× with ethyl acetate, and the combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by silica gel chromatography (10:1 to 2:1 hexane-ethylacetate), affording (2,3-Difluoro-4-methyl-phenyl)-methanol as a lightyellow oil.

1-Bromo-2,5-difluoro-4-methyl-benzene

A mixture of 2,5-difluorotoluene (25 g, 0.20 mol) and iron powder (11 g,0.2 mol) was cooled to −5° C. Bromine was added dropwise such that theinternal temperature of the reaction did not rise above 0° C. Afterstirring for 3 hours, the mixture was diluted with ether, filtered andwashed with aqueous sodium thiosulfate solution. The aqueous layer wasextracted with ether, and the combined organic layers were dried overMgSO₄, filtered and concentrated in vacuo. Distillation at atmosphericpressure gave 34 g of 1-bromo-2,5-difluoro-4-methyl-benzene as acolorless oil (b.p. 180° C.). ¹H NMR (300 MHz, CDCl₃) δ7.20 (dd, 1H,J=6.0, 8.5 Hz), 6.93 (m, 1H), 2.23 (s, 3H) ppm.

(2,5-Difluoro-4-methyl-phenyl)-methanol

A mixture of 1-bromo-2,5-difluoro-4-methyl-benzene (3.3 g, 16 mmol) andether (75 mL) was cooled to −78° C., and a solution of n-butyllithium inhexane (5.4 mL, 2.5 M, 13.5 mmol) was added dropwise. After stirring for1 hour, dimethylformamide (1.1 mL, 14 mmol) was added, and the mixturewas stirred for 1 hour. The mixture was treated with 1M HCl and water,warmed to ambient temperature and was extracted 3× with ether. Thecombined organic layers were dried over MgSO₄, filtered and concentratedin vacuo. The residue was diluted with tetrahydrofuran (50 mL), and themixture was treated with sodium borohydride (0.50 g, 13.5 mmol) andethanol (2 mL). After stirring for 30 minutes, the mixture was dilutedcautiously with 0.5M aqueous HCl, extracted 3× with ethyl acetate, andthe combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. Recrystallization of the residue from hexaneafforded 1.24 g (54%) of (2,5-difluoro-4-methyl-phenyl)-methanol as acolorless solid. ¹H NMR (400 MHz, CDCl₃) δ7.05 (dd, 1H, J=6.0, 9.2 Hz),6.84 (dd, 1H, J=6.4, 10 Hz), 4.68 (d, 2H, J=6.0 Hz), 2.23 (s, 3H), 1.76(t, 1H, J=6.0 Hz) ppm.

(5-Chloro-2-fluoro-4-methyl-phenyl)-methanol

(5-Chloro-2-fluoro-4-methyl-phenyl)-methanol was prepared in analogousfashion to (2,5-difluoro-4-methyl-phenyl)-methanol using2-chloro-5-fluorotoluene as starting material. ¹H NMR (400 MHz, CDCl₃)δ7.38 (d, 1H, J=6.8 Hz), 6.92 (d, 1H, J=10 Hz), 4.69 (s, 2H), 2.34 (s,3H) ppm.

4-Chloro-2,6-difluoro-benzaldehyde

To a solution of 3,5-difluoro-1-chlorobenzene (5.0 g, 34 mmol) intetrahydrofuran (70 mL) at −78° C. was added a solution ofn-butyllithium in hexane (12.1 mL, 2.5 M, 30 mmol). After stirring for 1hour, dimethylformamide (5.2 mL, 67 mmol) was added, and the mixture wasstirred for 1.5 hours. The mixture was warmed to ambient temperature,diluted with ether and poured into 150 mL of 0.5 M aqueous HCl. Theaqueous phase was extracted 3× into ether, and the combined organiclayers were dried over MgSO₄, filtered and concentrated in vacuo,affording 5.72 g (96%) of 4-chloro-2,6-difluoro-benzaldehyde as acolorless solid. ¹H NMR (400 MHz, CDCl₃) δ10.27 (s, 1H), 7.04 (d, 2H,J=7.9 Hz) ppm.

(4-Chloro-2,6-difluoro-phenyl)-methanol

To a mixture of 4-chloro-2,6-difluoro-benzaldehyde (5.7 g, 32 mmol),tetrahydrofuran (150 mL) and ethanol (20 mL) was added sodiumborohydride (1.2 g, 32 mmol) at 0° C. The mixture was stirred for 30minutes, warmed to ambient temperature, and additional sodiumborohydride (0.40 g, 11 mmol) was added to drive the reaction tocompletion (TLC). The mixture was concentrated in vacuo, diluted withether and treated cautiously with 1M aqueous HCl. The aqueous phase wasextracted 3× with ether, and the combined organic layers were dried overMgSO₄, filtered and concentrated. Trituration of the residue withpentane afforded 4.8 g (83%) of (4-chloro-2,6-difluoro-phenyl)-methanolas a colorless solid. ¹H NMR (300 MHz, CDCl₃) δ7.04 (d, 2H, J=7.1 Hz),4.73 (s, 2H) ppm.

General Procedure for the Preparation of Isothiazole Phenyl Carbamates:[4-Carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester

35 To a mixture of (4-carbamoyl-3-hydroxy-isothiazol-5-yl)-carbamic acidphenyl ester (2.1 g, 7.6 mmol), (2,5-difluoro-4-methyl-phenyl)-methanol(1.2 g, 7.6 mmol), triphenylphosphine (2.1 g, 8.0 mmol) andtetrahydrofuran (19 mL) was added diethylazodicarboxylate (1.3 mL, 8.0mmol). After stirring for 16 hours at ambient temperature, additional(2,5-difluoro-4-methyl-phenyl)-methanol (0.24 g, 1.5 mmol),triphenylphosphine (0.42 g, 1.6 mmol) and diethylazodicarboxylate (0.30mL, 1.8 mmol) were added, and the mixture was stirred for 1 hour. Afterconcentrating in vacuo, the mixture was purified by silica gelchromatography eluting with acetone-acetic acid-methylene chloride(0.5%, 0.5%, 99%), affording, after trituration from ether-hexane, 1.1 g(35%) of[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester as a colorless solid. HPLC ret. time: 4.8 min. ¹H NMR(400 MHz, CD₃OD) δ7.40 (t, 2H, J=8.0 Hz), 7.27 (t, 1H, J=7.2 Hz), 7.20(d, 2H, J=8.4 Hz), 7.17 (dd, 1H, J=6.0,9.2 Hz), 7.00 (dd, 1H, J=6.4, 10Hz), 5.49 (s, 2H), 2.24 (s, 3H) ppm.

[4-Carbamoyl-3-(2,3-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester

Preparation of the title compound as described for example 3 using(2,3-difluoro-4-methyl-phenyl)-methanol afforded 1.7 g (57%) of[4-carbamoyl-3-(2,3-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester as a colorless solid. HPLC ret. time: 4.8 minutes. ¹HNMR (400 MHz, CDCl₃) δ11.38 (s, 1H), 7.40 (t, 2H, J=8.0 Hz), 7.26 (t,1H, J=7.2 Hz), 7.20 (d, 1H, J=8.4 Hz), 7.14 (b, 1H), 7.11 (t, 1H, J=7.6Hz), 6.94 (t, 1H, J=7.2 Hz), 5.6 (b, 1H), 5.52 (s, 2H), 2.31 (d, 3H,J=1.7 Hz) ppm.

[4-Carbamoyl-3-(2,5-difluoro-4chloro-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester

Preparation of the title compound as described for example 3 using(2,5-difluoro-4-chloro-phenyl)-methanol afforded 0.86 g (26%) of[4-carbamoyl-3-(2,5-difluoro-4-chloro-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester as a colorless solid. HPLC ret. time: 4.8 minutes. ¹HNMR (400 MHz, DMSO-d₆) δ11.73 (s, 1H), 8.04 (s, 1H), 7.77 (m, 2H), 7.51(m, 2H), 7.36 (m, 3H), 7.23 (s, 1H), 5.51 (s, 2H) ppm.

[4-Carbamoyl-3-(2,6-difluoro-4-chloro-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester

Preparation of the title compound as described for example 3 using(2,6-difluoro-4-chloro-phenyl)-methanol afforded 0.86 g (26%) of[4-carbamoyl-3-(2,6-difluoro-4-chloro-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester as a colorless solid. HPLC ret. time: 4.5 minutes. ¹HNMR (400 MHz, CDCl₃, CD₃OD) δ7.31 (t, 2H, J=8.0 Hz), 7.18 (t, 1H, J=7.6Hz), 7.10 (d, 2H, J=7.6 Hz), 6.92 (d, 2H, J=7.2 Hz), 5.45 (s, 2H) ppm.

General Procedure for the Preparation of Isothiazole Ureas EXAMPLE 63-(2,5-difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-ylbutyl)-ureido]-isothiazole-4-carboxylic acid amide

A mixture of[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester (0.34 g, 0.81 mmol), 4-pyrrolidinobutylamine (0.12 g,0.81 mmol) and tetrahydrofuran (2.8 mL) was shaken at 45-50° C. for 24hours. The mixture was concentrated and purified by radialchromatography (4 mm plate, CH₃OH—CHCl₃—NH₄OH (10:89:1) to (15:84:1)),affording 0.31 g of the title compound as a colorless solid. Thematerial was dissolved in ca. 10 mL of 4:1 methanol-chloroform at −10°C. and was treated with a solution of methanesulfonic acid (0.043 mL in0.5 mL of CH₃OH). After stirring for 5 minutes, the mixture wasconcentrated in vacuo, and the residue was triturated withmethanol-ether, affording 0.35 g of the title compound (82%) as acolorless solid. HPLC ret. time: 3.3 minutes. ¹H NMR (400 MHz, D₂O)δ6.74 (dd, 1H, J=6.0, 9.6 Hz), 6.63 (dd, 1H, J=6.4, 10.4 Hz), 4.61 (s,2H), 3.44 (m, 2H), 3.05-2.98 (m, 4H), 2.98-2.81 (m, 2H), 2.62 (s, 3H),195-193 (m, 4H), 1.83-1.80 (m, 2H), 1.6-1.5 (m, 2H), 1.4-1.3 (m, 2H)ppm; MS (APCI, m/z): 468 [M+H]⁺.

EXAMPLE 73-(2,5-difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 5-amino-1-piperidin-1-yl-pentan-2-ol by theprocedure analogous to Example 6. HPLC ret. time: 3.3 minutes. ¹H NMR(400 MHz, CD₃OD) δ7.18 (dd, 1H, J=6.0, 9.2 Hz), 7.05 (dd, 1H, J=6.0, 10Hz), 5.47 (s, 2H), 3.80 (m, 1H), 3.23 (t, 2H, J=6.4 Hz), 2.7-2.4 (m,7H), 2.25 (s, 3H), 1.8-1.4 (m, nH) ppm; Ms (APCI, m/z): 512 [M+H]⁺.

EXAMPLE 8(R)-3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and (R)-1-(4-amino-butyl)-pyrrolidin-3-ol by theprocedure analogous to Example 6. HPLC ret. time: 3.2 minutes. ¹H NMR(400 MHz, CD₃OD) δ7.19 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.0, 10Hz), 5.45 (s, 2H), 4.34 (m, 1H), 3.23 (m, 2H), 2.86 (dd, 1H, J=6.0, 10.4Hz), 2.78 (m, 1H), 2.65-2.54 (m, 4H), 2.25 (s, 3H), 2.14 (m, 1H), 1.73(m, 1H), 1.56 (m, 4H) ppm; MS (APCI, m/z): 484 [M+H]⁺.

EXAMPLE 93-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and N1,N1-Dimethyl-hexane-1,6-diamine by the procedureanalogous to Example 6. HPLC ret. time: 3.4 minutes. ¹H NMR (400 MHz,CD₃OD) δ7.18 (dd, 1H, J=6.0, 9.2 Hz), 7.03 (dd, 1H, J=6.4, 10 Hz), 5.45(s, 2H), 3.19 (t, 2H, J=7.2 Hz), 2.28 (m, 2H), 2.24 (s, 3H), 2.22 (s,6H), 1.55-1.45 (m, 4H), 1.35-1.33 (m, 4H) ppm; MS (APCI, m/z): 470[M+H]⁺.

EXAMPLE 103-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido{-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and (S)-[1-(4-amino-butyl)-pyrrolidin-2-yl]-methanolby the procedure analogous to Example 6. HPLC ret. time: 3.2 minutes. ¹HNMR (400 MHz, CD₃OD) δ7.18 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.4,10 Hz), 5.45 (s, 2H), 3.62-3.56 (m, 2H), 3.29-3.23 (m, 2H), 3.02 (m,1H), 2.78 (m, 1H), 2.83 (m, 1H), 2.51 (m, 2H), 2.24 (d, 3H, J=1.6 Hz),2.02 (m, 1H), 1.88-1.56 (m, 7H) ppm; MS (APCI, m/z): 498 [M+H]⁺.

EXAMPLE 113-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[-4-(3-hydroxy-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 1-(4-amino-butyl)-piperidin-3-ol by the procedureanalogous to Example 6. HPLC ret. time: 3.3 minutes. ¹H NMR (400 MHz,CD₃OD) δ7.18 (dd, 1H, J=6.8, 9.6 Hz), 7.04 (dd, 1H, J=5.6, 10 Hz), 5.45(s, 2H), 3.64 (m, 1H), 3.24-3.22 (m, 2H), 2.90 (m, 1H), 2.73 (m, 1H),2.37 (m, 2H), 2.25 (d, 3, J=1.6 Hz), 1.99-1.87 (m, 3H), 1.74 (m, 1H),1.74-1.53 (m, 6H) ppm; MS (APCI, m/z): 498 [M+H]⁺.

EXAMPLE 123-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and N1-lsopropyl-pentane-1,5-diamine by the procedureanalogous to Example 6. HPLC ret. time: 3.4 minutes. ¹H NMR (300 MHz,CD₃OD) δ7.20 (dd, 1H, J=5.7, 9.0 Hz), 7.06 (dd, 1H, J=6.3, 10 Hz), 5.47(s, 2H), 3.23 (t, 2H, J=6.6 Hz), 2.93 (s, 1H, J=6.3 Hz), 2.70 (m, 2H),2.27 (d, 3H, J=1.8 Hz), 1.7-1.5 (m, 4H), 1.5-1.3 (m, 2H), 1.11 (d, 6H,J=6.6 Hz) ppm; MS (APCI, m/z): 470 [M+H]⁺.

EXAMPLE 133-(2,3-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 1-(4-amino-butyl)-pyrrolidine-3,4-diol by theprocedure analogous to Example 6. HPLC ret. time: 3.1 minutes. ¹H NMR(400 MHz, CD₃OD) δ7.17 (t, 1H, J=7.6 Hz), 7.03 (t, 1H, J=7.3 Hz), 5.49(s, 2H), 4.01 (s, 2H), 3.21 (s, 2H), 2.93 (m, 2H), 2.48 (m, 4H), 2.29(s, 3H), 1.54 (bs, 4H) ppm; MS (APCI, m/z): 500 [M+H]⁺.

EXAMPLE 143-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide—Methanesulfonate Salt

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol by theprocedure analogous to Example 6. HPLC ret. time: 3.1 minutes. ¹H NMR(400 Mhz, D₂O ) δ6.81 (d, 2H, J=7.2 Hz), 5.17 (s, 2H), 3.61 (bm, 1H),3.47 (bm, 2H), 3.2-3.0 (m, 4H), 2.89 (m, 2H), 2.62 (s, 3H), 1.94 (m,2H), 1.85-1.2 (m, 6H) ppm; MS (APCI, m/z): 518 [M+H]⁺.

EXAMPLE 153-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide—Methanesulfonate Salt

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol by theprocedure analogous to Example 6. HPLC ret. time: 3.3 minutes. ¹H NMR(400 MHz, CD₃OD) δ7.17 (d, 2H, J=6.4 Hz), 5.51 (s, 2H), 3.64 (bm, 1H),3.24 (t, 2H, J=6.0 Hz), 2.92 (m, 1H), 2.72 (m, 1H), 2.39 (m, 2H), 1.98(m, 1H), 1.87 (m, 2H), 1.75 (m, 1H), 1.54 (m, 4H), 1.22 (m, 2H) ppm; MS(APCI, m/z): 517 [M+H]⁺.

EXAMPLE 163-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide—Methanesulfonate Salt

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol by theprocedure analogous to Example 6. HPLC ret. time: 3.3 minutes. ¹H NMR(400 MHz, CD₃OD) δ7.17 (d, 2H, J=6.4 Hz), 5.51 (s, 2H), 3.64 (bm, 1H),3.24 (t, 2H, J=6.0 Hz), 2.92 (m, 1H), 2.72 (m, 1H), 2.39 (m, 2H), 1.98(m, 1H), 1.87 (m, 2H), 1.75 (m, 1H), 1.54 (m, 4H), 1.22 (m, 2H) ppm; MS(APCI, m/z): 517 [M+H⁺.

EXAMPLE 175-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and2-[(4-amino-butyl)-(2-hydroxy-ethyl)-amino]-ethanol by the procedureanalogous to Example 6. HPLC ret. time: 3.1 minutes. ¹H NMR (400 MHz,CD₃OD) δ7.20 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.8, 9.6 Hz), 5.45(s, 2H), 3.63 (t, 4H, J=5.6 Hz), 3.28 (m), 2.74 (m, 4H), 2.68 (m, 2H),2.25 (d, 3H, J=2.0 Hz), 1.56 (m, 4H) ppm; MS (APCI, m/z): 502 [M+H]⁺.

EXAMPLE 183-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]carbamicacid phenyl ester and 1-(4-amino-butyl)-pyrrolidine-3,4-diol by theprocedure analogous to Example 8. HPLC ret. time: minutes. ¹H NMR (400MHz, CD₃OD) δ7.20 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.8, 9.6 Hz),5.45 (s, 2H), 3.63 (t, 4H, J=5.6 Hz), 3.28 (m), 2.74 (m, 4H), 2.68 (m,2H), 2.25 (d, 3H, J=2.0 Hz), 1.56 (m, 4H) ppm.

EXAMPLE 195-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 4-amino-1-tert-butylamino-butan-2-ol by theprocedure analogous to Example 6. HPLC ret. time: 3.3 minutes. ¹H NMR(400 MHz, CD₃OD) δ7.18 (dd, 1H, J=6.8, 9.6 Hz), 7.04 (dd, 1H, J=6.4, 10Hz), 5.45 (s, 2H), 3.66 (m, 1H), 3.34 (t, 2H, J=7.6 Hz), 2.58 (m, 2H),2.25 (s, 3H), 1.69-1.60 (m, 2H), 1.12 (s, 9H) ppm; MS (APCI, m/z): 486[M+H]⁺.

EXAMPLE 203-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide—Hydrochloride Salt

The title compound was prepared from[4-carbamoyl-3-(2,6-difluoro-4-chloro-benzyloxy)-isothiazol-5-yl]carbamicacid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by theprocedure analogous to Example 6. ¹H NMR (400 MHz, D₂O) δ6.86 (bm, 2H),5.20 (s, 2H), 3.4-2.6 (bm, 8H), 3.10 (b, 2H), 2.63 (b, 5H), 1.67 (m, 2H)ppm; MS (APCI m/z): 503 [M+H]⁺.

EXAMPLE 213-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,6-difluoro-4-chloro-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and1-amino-5-isopropylamino-pentan-3-ol by the procedure analogous toExample 6. HPLC ret. time: 3.2 minutes. ¹H NMR (400 MHz, CD₃OD) δ7.17(d, 1H, J=7.6 Hz), 5.52 (s, 2H), 3.69 (m, 1H), 3.34 (t, 2H, J=6.4 Hz),2.80 (s, 1H, J=6.0 Hz), 2.73 (m, 2H), 1.68-1.58 (m, 4H), 1.06 (d, 6H,J=6.0 Hz) ppm; MS (APCI, m/z): 506 [M+H]⁺.

EXAMPLE 223-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,6-difluoro-4-chloro-benzyloxy)-isothiazol-5-yl]carbamicacid phenyl ester and 1-amino-5-isopropylamino-pentan-3-ol by theprocedure analogous to Example 6. HPLC ret. time: 3.2 minutes. ¹H NMR(400 MHz, CD₃OD) δ7.17 (d, 1H, J=7.6 Hz), 5.52 (s, 2H), 3.69 (m, 1H),3.34 (t, 2H, J=6.4 Hz), 2.80 (s, 1H, J=6.0 Hz), 2.73 (m, 2H), 1.68-1.58(m, 4H), 1.06 (d, 6H, J=6.0 Hz) ppm; MS (APCI, m/z): 506 [M+H]⁺.

EXAMPLE 233-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 2-[4-(6-amino-hexyl)-piperazin-1-yl]-ethanol bythe procedure analogous to Example 6. HPLC ret. time: 3.0 minutes. ¹HNMR (400 MHz, CD₃OD) δ7.17 (d, 1H, J=6.4, 9.6 Hz), 7.01 (m, 1H), 5.44(s, 2H), 3.64 (t, 2H, J=5.6 Hz), 3.18 (t, 2H, J=6.8 Hz), 2.7-2.4 (bm,8H), 2.50 (t, 2H, J=6.0 Hz), 2.33 (m, 2H), 2.23 (s, 3H), 1.50 (m, 4H),1.35 (m, 4H) ppm; MS (APCI, m/z): 555 [M+H]⁺.

EXAMPLE 243-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 2-[4-(6-amino-hexyl)-piperazin-1-yl]-ethanol bythe procedure analogous to Example 6. HPLC ret. time: 3.0 minutes. ¹HNMR (400 MHz, CD₃OD) δ7.17 (d, 1H, J=6.4, 9.6 Hz), 7.01 (m, 1H), 5.44(s, 2H), 3.64 (t, 2H, J=5.6 Hz), 3.18 (t, 2H, J=6.8 Hz), 2.7-2.4 (bm,8H), 2.50 (t, 2H, J=6.0 Hz), 2.33 (m, 2H), 2.23 (s, 3H), 1.50 (m, 4H),1.35 (m, 4H) ppm; MS (APCI, m/z): 555 [M+H]⁺.

EXAMPLE 255-{3-[3-(4-Methyl-piperazin-1-yl)-propyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by theprocedure analogous to Example 1. MS (APCI, m/z): 501 [M+H]⁺.

EXAMPLE 263-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2-fluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by theprocedure analogous to Example 1. MS (APCI, m/z): 465 [M+H]⁺.

EXAMPLE 273-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2-fluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and N-isopropyl-pentane-1,5-diamine by the procedureanalogous to Example 1. MS (APCI, m/z): 452 [M+H]⁺.

EXAMPLE 283-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from(4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedureanalogous to Example 1. ¹H NMR (400 MHz, CDCl₃) δ1.63 (br. s, 4H), 1.83(br. s, 4H), 2.34 (s, 3H), 2.46-2.52 (m, 6H), 3.28 (s, 2H), 5.40 (s,1H), 5.50 (s, 2H), 6.74 (d, J=8.3 Hz, 2H), 6.98 (s, 1H), 7.94 (br. s,1H), 10.83 (br. s, 1H) ppm; MS (APCI, m/z): 468 [M+H]⁺.

EXAMPLE 293-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 2-[4-(4-amino-butyl)-piperazin-1-yl]-ethanol bythe procedure analogous to Example 1. MS (APCI, m/z): 527 [M+H]⁺.

EXAMPLE 303-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[3-(4-bromo-2,6-difluoro-benzyloxy)4-carbamoyl-isothiazol-5-yl]-carbamicacid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedureanalogous to Example 1. MS (APCI, m/z): 532 and 534 [M+H]⁺.

EXAMPLE 313-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 5-amino-1-piperidin-1-yl-pentan-2-ol by theprocedure analogous to Example 1. MS (APCI, m/z): 512 [M+H]⁺.

EXAMPLE 323-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide

The title compound was prepared from[3-(4-bromo-2,3,6-trifluoro-benzyloxy)-4-carbamoyl-isothiazol-5-yl]-carbamicacid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by theprocedure analogous to Example 1. MS (APCI, m/z): 565 and 567 [M+H]⁺.

EXAMPLE 333-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-Carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and and 3-(4-methyl-piperazin-1-yl)-propylamine by theprocedure analogous to Example 1. MS (APCI, m/z): 483 [M+H]⁺.

EXAMPLE 343-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol by theprocedure analogous to Example 1. MS (APCI, m/z): 498 [M+H]⁺.

EXAMPLE 355-[3-(4-Pyrrolidin-1-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedureanalogous to Example 1. MS (APCI, m/z): 486 [M+H]⁺.

EXAMPLE 365-[3-(3-Hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol by theprocedure analogous to Example 1. MS (APCI, m/z): 516 [M+H]⁺.

EXAMPLE 375-{3-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 2-(1-methyl-pyrrolidin-2-yl)-ethylamine by theprocedure analogous to Example 1. MS (APCI, m/z): 472 [M+H]⁺.

EXAMPLE 385-[3-(4-Dimethylamino-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and N,N-dimethyl-butane-1,4-diamine by the procedureanalogous to Example 1. MS (APCI, m/z): 460 [M+H]⁺.

EXAMPLE 395-[3-(3-Dimethylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and N,N-dimethyl-propane-1,3-diamine by the procedureanalogous to Example 1. MS (APCI, m/z): 446 [M+H]⁺.

EXAMPLE 405-[3-(3-Hydroxy-5-isopropylamino-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 1-amino-5-isopropylamino-pentan-3-ol by theprocedure analogous to Example 1. MS (APCI, m/z): 504 [M+H]⁺.

EXAMPLE 415-[3-(3-Isopropylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and N-isopropyl-propane-1,3-diamine by the procedureanalogous to Example 1. MS (APCI, m/z): 460 [M+H]⁺.

EXAMPLE 425-{3-[4-(4Methyl-piperazin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 4-(4-methyl-piperazin-1-yl)-butylamine by theprocedure analogous to Example 1. MS (APCI, m/z): 515 [M+H]⁺.

EXAMPLE 435-(3-{4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 2-[4-(4-amino-butyl)-piperazin-1-yl]-ethanol bythe procedure analogous to Example 1. MS (APCI, m/z): 545 [M+H]⁺.

EXAMPLE 445-[3-(3-Pyrrolidin-1-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 3-pyrrolidin-1-yl-propylamine by the procedureanalogous to Example 1. MS (APCI, m/z): 472 [M+H]⁺.

EXAMPLE 455-[3-(4-Hydroxy-5-piperidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 5-amino-1-piperidin-1-yl-pentan-2-ol by theprocedure analogous to Example 1. MS (APCI, m/z): 530 [M+H]⁺.

EXAMPLE 465-(3-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 2-[(4-amino-butyl)-ethyl-amino]-ethanol by theprocedure analogous to Example 1. MS (APCI, m/z): 504 [M+H]⁺.

EXAMPLE 473-(4-Bromo-2,6-difluoro-benzyloxy)-1-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide

The title compound was prepared from[3-(4-bromo-2,6-difluoro-benzyloxy)-4-carbamoyl-isothiazol-5-yl]-carbamicacid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by theprocedure analogous to Example 1. MS (APCI, m/z): 547 and 549 [M+H]⁺.

EXAMPLE 483-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 2-(1-methyl-pyrrolidin-2-yl)-ethylamine by theprocedure analogous to Example 1. MS (APCI, m/z): 454 [M+H]⁺.

EXAMPLE 493-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and N,N-dimethyl-butane-1,4-diamine by the procedureanalogous to Example 1. MS (APCI, m/z): 442 [M+H]⁺.

EXAMPLE 50

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-dimethylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and N,N-dimethyl-propane-1,3-diamine by the procedureanalogous to Example 1. MS (APCI, m/z): 428 [M+H]⁺.

EXAMPLE 513-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[3-(4-bromo-2,3,6-trifluoro-benzyloxy)4-carbamoyl-isothiazol-5-yl]-carbamicacid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedureanalogous to Example 1. MS (APCI, m/z): 550 and 552 [M+H]⁺.

EXAMPLE 525-[3-(3-Methylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbonicacid phenyl ester and N-methyl-propane-1,3-diamine by the procedureanalogous to Example 1. MS (APCI, m/z): 432 [M+H]⁺.

EXAMPLE 535-[3-(3-Amino-propyl)-3-methyl-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and N-methyl-propane-1,3-diamine by the procedureanalogous to Example 1. MS (APCI, m/z): 432 [M+H]⁺.

EXAMPLE 545-[3-(4-Diethylamino-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and N,N-diethyl-butane-1,4-diamine by the procedureanalogous to Example 1. MS (APCI, ml) 488 [M+H]⁺.

EXAMPLE 553-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and 3-pyrrolidin-1-yl-propylamine by the procedureanalogous to Example 1. MS (APCI, m/z): 454 [M+H]⁺.

EXAMPLE 563-(3-Chloro-2,6-difluoro-4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido]-isothiazole-4-carboxylicacid amide

The title compound was prepared[4-carbamoyl-3-(3-chloro-2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and N,N-diethyl-butane-1,4-diamine by the procedureanalogous to Example 1. MS (APCI, m/z): 476 [M+H]⁺.

EXAMPLE 575-(3{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide

The title compound was prepared from[4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamicacid phenyl ester and2-[(4-amino-butyl)-(2-hydroxy-ethyl)-amino]-ethanol by the procedureanalogous to Example 1. MS (APCI, m/z): 502 [M+H]⁺.

The following specific compounds were prepared using the generalsynthetic procedures described above with reference to Schemes 1-5 andthe specific synthetic procedures described in the above preparationsand examples.

(3-tert-Butyl-isothiazol-5-yl)-(6,7-dimethoxy-quinolin-4-yl)-amine;

3-Ethylsulfanyl-5-(3-hexyl-ureido)-isothiazole-4-carboxylic acid amide;

5-(3-Benzyl-ureido)-3-ethylsulfanyl-isothiazole-4-carboxylic acid amide;

3-Ethylsulfanyl-5-(3-ethyl-ureido)-isothiazole-4-carboxylic acid amide;

3-Ethylsulfanyl-5-[(pyrrolidine-1-carbonyl)-amino]-isothiazole-4-carboxylicacid amide;

5-(3-Butyl-ureido)-3-ethylsulfanyl-isothiazole-4-carboxylic acid amide;

5-(3,3-Dimethyl-ureido)-3-propylsulfanyl-isothiazole-4-carboxylic acidamide;

5-(3-Methyl-ureido)-3-propylsulfanyl-isothiazole-4-carboxylic acidamide;

5-(3-Butyl-ureido)-3-propylsulfanyl-isothiazole-4-carboxylic acid amide;

5-(3-Methyl-ureido)-3-pentylsulfanyl-isothiazole-4-carboxylic acidamide;

5-(3,3-Dimethyl-ureido)-3-pentylsulfanyl-isothiazole-4-carboxylic acidamide;

5-(3,3-Dimethyl-ureido)-3-isopropylsulfanyl-isothiazole-4-carboxylicacid amide;

3-Pentylsulfanyl-5-ureido-isothiazole-4-carboxylic acid amide;

3-Benzylsulfanyl-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylic acidamide;

5-(3,3-Dimethyl-ureido)-3-propoxy-isothiazole-4-carboxylic acid amide;

(3-Butoxy-4-carbamoyl-isothiazol-5-yl)-carbamic acid ethyl ester;

5-(3,3-Dimethyl-ureido)-3-phenethylsulfanyl-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-hexylsulfanyl-isothiazole-4-carboxylic acidamide;

3-(4-Chloro-butylsulfanyl)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-Butoxy-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylic acid amide;

3-Butylsulfanyl-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylic acidamide;

3-Cyclohexylsulfanyl-5-(3-methyl-ureido)-isothiazole-4-carboxylic acidamide;

5-(3,3-Dimethyl-ureido)-3-(3-methyl-butylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-pentyloxy-isothiazole-4-carboxylic acid amide;

5-(3,3-Dimethyl-ureido)-3-prop-2-ynylsulfanyl-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-heptylsulfanyl-isothiazole-4-carboxylic acidamide;

5-(3,3-Dimethyl-ureido)-3-isobutylsulfanyl-isothiazole-4-carboxylic acidamide;

5-(3-Methyl-ureido)-3-phenylsulfanyl-isothiazole-4-carboxylic acidamide;

5-(3,3-Dimethyl-ureido)-3-(3-hydroxy-butylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-Amino-3-propoxy-isothiazole-4-carboxylic acid amide;

3-Propoxy-5-(3-propyl-ureido)-isothiazole-4-carboxylic acid amide;

5-(3-Butyl-ureido)-3-propoxy-isothiazole-4-carboxylic acid amide;

5-(3-Ethyl-ureido)-3-propoxy-isothiazole-4-carboxylic acid amide;

5-(3-Pentyl-ureido)-3-propoxy-isothiazole-4-carboxylic acid amide;

5-(3-Hexyl-ureido)-3-propoxy-isothiazole-4-carboxylic acid amide;

5-[(Azetidine-1-carbonyl)-amino]-3-propoxy-isothiazole-4-carboxylic acidamide;

Piperidine-1-carboxylic acid(4-carbamoyl-3-propoxy-isothiazol-5-yl)-amide;

5-(3-Phenethyl-ureido)-3-propoxy-isothiazole-4-carboxylic acid amide;

3-Propoxy-5-[(pyrrolidine-1-carbonyl)-amino]-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-methylsulfanyl-isothiazole-4-carboxylic acidamide;

3-Cyclopentylsulfanyl-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Benzyl-ureido)-3-propoxy-isothiazole-4-carboxylic acid amide;

5-(3,3-Dimethyl-ureido)-3-(naphthalen-1-ylmethylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-[4-Carbamoyl-5-(3,3-dimethyl-ureido)-isothiazol-3-ylsulfanyl]-propionicacid;

3-Propoxy-5-ureido-isothiazole-4-carboxylic acid amide;

3-Propoxy-5-(3-pyridin-3-yl-ureido)-isothiazole-4-carboxylic acid amide;

5-(3,3-Dimethyl-ureido)-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(4-methoxy-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(4-methyl-pentylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-(3-Butyl-ureido)-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide;

5-Acetylamino-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide;

5-Benzoylamino-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide;

3-Decyloxy-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylic acid amide;

Morpholine-4-carboxylic acid(4-carbamoyl-3-pentylsulfanyl-isothiazol-5-yl)-amide;

5-[3-(2-Hydroxy-ethyl)-ureido]-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

5-[(3-Hydroxy-azetidine-1-carbonyl)-amino]-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

5-[3-(3-Hydroxy-propyl)-ureido]-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

3-Pentylsulfanyl-5-(3-propyl-ureido)-isothiazole-4-carboxylic acidamide;

5-(3,3-Dimethyl-ureido)-3-hexyloxy-isothiazole-4-carboxylic acid amide;

5-(3,3-Dimethyl-ureido)-3-heptyloxy-isothiazole-4-carboxylic acid amide;

5-(3-Isobutyl-ureido)-3-pentylsulfanyl-isothiazole-4-carboxylic acidamide;

5-(3-Furan-2-ylmethyl-ureido)-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-octyloxy-isothiazole-4-carboxylic acid amide;

5-(3,3-Dimethyl-ureido)-3-(3-methyl-benzyloxy)-isothiazole-4- carboxylicacid amide;

3-Allyloxy-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylic acid amide;

5-(3,3-Dimethyl-ureido)-3-nonyloxy-isothiazole-4-carboxylic acid amide;

5-(3,3-Dimethyl-ureido)-3-(naphthalen-2-ylmethylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(3-methyl-but-2-enyloxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(3-phenyl-allyloxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-pent-2-enyloxy-isothiazole-4-carboxylic acidamide;

5-(3,3-Dimethyl-ureido)-3-(2-methyl-allyloxy)-isothiazole-4-carboxylicacid amide;

3-Benzyloxy-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylic acid amide;

5-(3,3-Dimethyl-ureido)-3-phenethyloxy-isothiazole-4-carboxylic acidamide;

3-(2-Cyclohexyl-ethoxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Ethyl-ureido)-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide;

5-[3-(3-Dimethylamino-propyl)-ureido]-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(2-fluoro-3-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(3-methoxy-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-Pentylsulfanyl-5-(3-thiophen-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Methyl-butyl)-ureido]-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

5-[3-(4-Hydroxy-butyl)-ureido]-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

5-[3-(3-Methoxy-propyl)-ureido]-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

4-Hydroxy-piperidine-1-carboxylic acid(4-carbamoyl-3-pentylsulfanyl-isothiazol-5-yl)-amide;

5-(3,3-Dimethyl-ureido)-3-(3-trifluoromethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(naphthalen-2-ylmethoxy)-isothiazole-4-carboxylicacid amide;

3-Heptyloxy-5-(3-methyl-ureido)-isothiazole-4-carboxylic acid amide;

3-(3,5-Dimethyl-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(2-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

[3-(4-Carbamoyl-3-pentylsulfanyl-isothiazol-5-yl)-ureido]-acetic acidmethyl ester;

5-[3-(5-Methyl-furan-2-ylmethyl)-ureido]-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

5-[3-(2-Hydroxy-propyl)-ureido-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

5-[(2,5-Dihydro-pyrrole-1-carbonyl)-amino]-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

5-{3-[2-(1H-Imidazol-4-yl)-ethyl]-ureido}-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

3-Pentylsulfanyl-5-[3-(tetrahydro-furan-2-ylmethyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(2-Cyano-ethyl)-ureido]-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

5-(3-Allyl-ureido)-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide;

5-[3-(2-Dimethylamino-ethyl)-ureido]-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-(3-isobutyl-ureido)-isothiazole-4-carboxylic acidamide;

3-Hexylsulfanyl-5-(3-propyl-ureido)-isothiazole-4-carboxylic acid amide;

5-(3,3-Dimethyl-ureido)-3-(3-fluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(3,5-Difluoro-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Butyl-ureido)-3-heptyloxy-isothiazole-4-carboxylic acid amide;

3-(3-Chloro-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(3-iodo-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(3-phenoxy-propoxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(4-phenoxy-butoxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(3-m-tolyl-propoxy)-isothiazole-4-carboxylicacid amide;

3-(5-Cyano-pentyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-methoxy-isothiazole-4-carboxylic acid amide;

3-(5-Chloro-pentyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Cyano-butoxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylic acidamide;

5-(3-Furan-2-ylmethyl-ureido)-3-hexylsulfanyl-isothiazole-4-carboxylicacid amide;

5-(3-Butyl-ureido)-3-hexylsulfanyl-isothiazole-4-carboxylic acid amide;

3-Hexylsulfanyl-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Pentylsulfanyl-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-[3-(2-hydroxy-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Benzylsulfanyl-5-(3-methyl-ureido)-isothiazole-4-carboxylic acidamide;

5-{3-[2-(1-Methyl-1H-pyrrol-2-yl)-ethyl]-ureido}-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

3-Benzylsulfanyl-5-(3-butyl-ureido)-isothiazole-4-carboxylic acid amide;

Benzoic acid2-[4-carbamoyl-5-(3,3-dimethyl-ureido)-isothiazol-3-yloxy]-ethyl ester;

5-(3,3-Dimethyl-ureido)-3-(2-phenoxy-ethoxy)-isothiazole-4-carboxylicacid amide;

3-(3-Benzyloxy-propoxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(3,3-diphenyl-propoxy)-isothiazole-4-carboxylicacid amide;

3-(6-Chloro-hexyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(2-ethoxy-ethoxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(4-vinyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-Cyclohexylmethoxy-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(4-phenyl-butoxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-[3-(3-methoxy-phenyl)-propoxy]-isothiazole-4-carboxylicacid amide;

3-(2,5-Dimethyl-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-}3-[2-(1H-imidazol-4-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-[3-(4-hydroxy-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Benzylsulfanyl-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Benzylsulfanyl-5-(3-benzyl-ureido)-isothiazole-4-carboxylic acidamide;

3-Benzylsulfanyl-5-(3-furan-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-Benzylsulfanyl-5-(3-isobutyl-ureido)-isothiazole-4-carboxylic acidamide;

3-Hexylsulfanyl-5-(3-pentyl-ureido)-isothiazole-4-carboxylic acid amide;

3-Hexylsulfanyl-5-(3-methyl-ureido)-isothiazole-4-carboxylic acid amide;

3-Hexylsulfanyl-5-[3-(3-methyl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-Ethyl-ureido)-3-hexylsulfanyl-isothiazole-4-carboxylic acid amide;

5-[3-(2-Morpholin-4-yl-ethyl)-ureido]-3-pentylsulfanyl-isothiazole-4-carboxylicacid amide;

5-[3-(2,3-Dihydroxy-propyl)-ureido]-3-heptyloxy-isothiazole-4-carboxylicacid amide;

3-Heptyloxy-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Heptyloxy-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Heptyloxy-5-[3-(5-hydroxy-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Heptyloxy-5-[3-(3-hydroxy-2,2-dimethyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Heptyloxy-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Heptyloxy-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Heptyloxy-5-[3-(2-hydroxy-ethyl)-ureido]-isothiazole-4-carboxylic acidamide;

3-Heptyloxy-5-[3-(4-hydroxy-butyl)-ureido]-isothiazole-4-carboxylic acidamide;

5-(3,3-Dimethyl-ureido)-3-(5-methyl-hexyloxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(naphthalen-1-ylmethoxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(3-phenyl-propoxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(4-methyl-pentyloxy)-isothiazole-4-carboxylicacid amide;

3-(3-Bromo-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(3,4-Dimethyl-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(3,5-Bis-trifluoromethyl-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Benzylsulfanyl-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-(3-furan-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Benzyl-ureido)-3-(4-chloro-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-(3-methyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Butyl-ureido)-3-(4-chloro-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(2-Dimethylamino-ethyl)-ureido]-3-hexylsulfanyl-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido-isothiazole-4-carboxylicacid amide;

5-[3-(3-Dimethylamino-propyl)-ureido]-3-hexylsulfanyl-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-{3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(2,3-dihydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(5-hydroxy-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(4-hydroxy-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(2-hydroxy-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(2,3-Dihydroxy-propyl)-ureido]-3-hexylsulfanyl-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-[3-(2-hydroxy-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Benzylsulfanyl-5-[3-(2,3-dihydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-[3-(5-hydroxy-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Benzylsulfanyl-5-[3-(2-hydroxy-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(2-hydroxy-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-Benzylsulfanyl-5-[3-(5-hydroxy-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

1-(4-Cyano-3-pentylsulfanyl-isothiazol-5-yl)-3-methyl-urea;5-(3,3-Dimethyl-ureido)-3-(2,4,6-trimethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(2-trifluoromethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(4-trifluoromethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzylsulfanyl)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(2-fluoro-benzylsulfanyl)-isothiazole-4-carboxylicacid amide,

5-(3,3-Dimethyl-ureido)-3-(3-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(2-fluoro-3-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Chloro-benzylsulfanyl)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

1-Methyl-3-[3-pentylsulfanyl-4-(1H-tetrazol-5-yl)-isothiazol-5-yl]-urea;

5-(3,3-Dimethyl-ureido)-3-(4-fluoro-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(3-Chloro-benzylsulfanyl)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Dimethyl-benzylsulfanyl)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(1-Bromo-naphthalen-2-ylmethylsulfanyl)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(3,4-Dimethyl-benzylsulfanyl)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(Biphenyl-4-ylmethoxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(2-fluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Chloro-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(4-isopropyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(2,3,4,5,6-pentamethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(2-dimethylamino-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(3-dimethylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-{3-[2-(1H-imidazol-4-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-{3-[2-(1-methyl-1H-pyrrol-2-yl)-ethyl)-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-{3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ureido}-isothiazol-4-carboxylicacid amide;

3-But-2-enyloxy-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylic acidamide;

5-(3,3-Dimethyl-ureido)-3-(4-methoxy-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,4-Difluoro-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-sec-Butyl-ureido)-3-(4-chloro-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(2,2-dimethyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(1-ethyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-(3-cyclopropylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(1-methyl-1-phenyl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzylsulfanyl)-5-[3-(3,4-difluoro-benzyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-tert-Butyl-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Isobutyl-ureido)-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-(3-Butyl-ureido)-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Hydroxy-propyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

(4-Carbamoyl-3-mercapto-isothiazol-5-yl)-carbamic acid phenyl ester;

5-(3-Butyl-ureido)-3-(3,4-dichloro-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(3,4-Dichloro-benzylsulfanyl)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(3,4-Dichloro-benzylsulfanyl)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

4-[4-Carbamoyl-5-(3-isobutyl-ureido)-isothiazol-3-ylsulfanylmethyl]-benzoicacid methyl ester;

4-[5-(3-Butyl-ureido)-4-carbamoyl-isothiazol-3-ylsulfanylmethyl]-benzoicacid methyl ester;

4-{4-Carbamoyl-5-[3-(3-hydroxy-propyl)-ureido-isothiazol-3-ylsulfanylmethyl}-benzoicacid methyl ester;

3-(3,3-Diphenyl-propylsulfanyl)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3,3-Diphenyl-propylsulfanyl)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Butyl-ureido)-3-(3,3-diphenyl-propylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(2-Dimethylamino-ethyl)-ureido]-3-(3,3-diphenyl-propylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-[3-(2-methoxy-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-[3-(2-pyridin-2-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Hexylsulfanyl-5-[3-(2-pyrrolidin-1-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3,3-Dimethyl-ureido)-3-(2-methoxy-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-Benzylsulfanyl-5-[3-(2-dimethylamino-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(2-Dimethylamino-ethyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(2-Dimethylamino-ethyl)-ureido]-3-(4-methoxy-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(2-Dimethylamino-ethyl)-ureido]-3-(3-methoxy-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(2-Dimethylamino-ethyl)-ureido]-3-(2-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(2-Dimethylamino-ethyl)-ureido]-3-(2-methoxy-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-{4-Carbamoyl-5-[3-(2-dimethylamino-ethyl)-ureido]-isothiazol-3-ylsulfanylmethyl}-benzoicacid methyl ester;

3-Benzylsulfanyl-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Methyl-benzylsulfanyl)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Methoxy-benzylsulfanyl)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Methoxy-benzylsulfanyl)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Methoxy-benzylsulfanyl)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

4-{4-Carbamoyl-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido-isothiazol-3-ylsulfanylmethyl}-benzoicacid methyl ester;

3-(2-Chloro-benzylsulfanyl)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-benzylsulfanyl)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-isobutyl-ureido)-3-(2-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-(3-isobutyl-ureido)-3-(3-methoxy-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-(3-Isobutyl-ureido)-3-(4-methoxy-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-(3-Isobutyl-ureido)-3-(3-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-benzylsulfanyl)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Fluoro-benzylsulfanyl)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-3-methyl-benzylsulfanyl)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,4-Difluoro-benzylsulfanyl)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethylsulfanyl)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(Benzo[1,3]dioxol-5-ylmethylsulfanyl)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-(3,4-dimethyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(3,4-Dimethyl-benzylsulfanyl)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzylsulfanyl)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzylsulfanyl)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(3,4-Dimethyl-benzylsulfanyl)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzylsulfanyl)-5-3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(3,4-Dimethyl-benzylsulfanyl)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(2,2-Dimethyl-propyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-(3,4-dichloro-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-(3-methoxy-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzylsulfanyl)-5-[3-(3,4-difluoro-benzyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(3,4-Difluoro-benzyl)-ureido]-3-(3,3-diphenyl-propylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(3,4-Difluoro-benzyl)-ureido]-3-(4-methoxy-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(3,4-Difluoro-benzyl)-ureido-3-(3,4-dimethyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(3-Methyl-benzylsulfanyl)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(2-Dimethylamino-ethyl)-ureido-3-(3-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(2-Dimethylamino-ethyl)-ureido-3-(3,4-dimethyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzylsulfanyl)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-{4-Carbamoyl-5-[3-(3,4-difluoro-benzyl)-ureido]-isothiazol-3-ylsulfanylmethyl}-benzoicacid methyl ester;

3-{4-Carbamoyl-5-[3-(3-hydroxy-propyl)-ureido]-isothiazol-3-ylsulfanylmethyl}-benzoicacid methyl ester;

5-[3-(3,4-Difluoro-benzyl)-ureido]-3-phenethylsulfanyl-isothiazole-4-carboxylicacid amide;

5-[3-(3,4-Difluoro-benzyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(3,4-Difluoro-benzyl)-ureido]-3-(2,4-dimethyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(4-tert-Butyl-benzylsulfanyl)-5-(3,3-dimethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Methyl-benzylsulfanyl)-5-[3-(2-phenyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(1,2-Dimethyl-propyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(3,5-Difluoro-benzyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-{3-[1-4-Fluoro-phenyl)-ethyl]-ureido}-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Fluoro-benzyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Fluoro-2-trifluoromethyl-benzyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

5-[3-(3Chloro-4-fluoro-benzyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-(3-butyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(2,2-dimethyl-propyl))-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-(3-furan-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Allyl-ureido)-3-(4-bromo-2-fluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-(3-cyclobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3,3-dimethyl-butyl)-ureido]-isothiezole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-(3-cyclopropylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-phenyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(2-Isopropylamino-ethyl)-ureido]-3-(4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-Cyclohexylmethyl-ureido)-3-(4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-Isobutyl-ureido)-3-(4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Dimethylamino-propyl)-ureido]-3-(4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethylsulfanyl)-5-[3-(3,4-difluoro-benzyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethylsulfanyl)-5-(3-cyclopropylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethylsulfanyl)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethylsulfanyl)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(3,4-Difluoro-benzyl)-ureido]-3-(5-methyl-thiophen-2-ylmethylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethoxy)-5-(3-cyclopropylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-isobutyl-ureido)-3-(5-methyl-thiophen-2-ylmethylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethoxy)-5-[3-(3,4-difluoro-benzyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-(5-methyl-thiophen-2-ylmethylsulfanyl)-isothiazole-4-carboxylicacid amide;

3-(5-Methyl-thiophen-2-ylmethylsulfanyl)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(5-Methyl-thiophen-2-ylmethylsulfanyl)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3,4-difluoro-benzyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(2-dimethylamino-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-dimethylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-(3-furan-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(2-pyrrolidin-1-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-{3-[2-(1H-imidazol-4-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(1-ethyl-pyrrolidin-2-ylmethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(2-isopropylamino-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-3-(3-diethylamino-2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(2-pyrrolidin-1-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(3,4-difluoro-benzyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-(2,3-dichloro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(2-sec-butylamino-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-benzyloxy)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-benzyloxy)-5-[3-(2-pyrrolidin-1-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-3-methyl-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-3-methyl-benzyloxy)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(2-Dimethylamino-propyl)-ureido]-3-(2-fluoro-3-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-3-methyl-benzyloxy)-5-[3-(2-pyrrolidin-1-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-3-methyl-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-benzyloxy)-5-[3-(2-dimethylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-3-methyl-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(5-methyl-furan-2-ylmethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Fluoro-2,4-dimethyl-benzyloxy)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(2-methyl-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(2-methyl-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Fluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Fluoro-4-methyl-benzyloxy)-5-[3-(2-methyl-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3,4-Dichloro-benzyloxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3,4-Dichloro-benzyloxy)-5-[3-(2-methyl-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Fluoro-4-methyl-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-benzyloxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-benzyloxy)-5-[3-(2-methyl-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(2-isopropylamino-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Fluoro-2,4-dimethyl-benzyloxy)-5-[3-(2-isopropylamino-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Fluoro-2,4-dimethyl-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(2-sec-Butylamino-ethyl)-ureido]-3-(3-fluoro-2,4-dimethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(3-Fluoro-2,4-dimethyl-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Fluoro-2,4-dimethyl-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(2-sec-Butylamino-ethyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(2-isopropylamino-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(3-Imidazol-1-yl-propyl)-ureido]-3-(4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(3,3-Dimethyl-butyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(2,2-Dimethyl-propyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(3-Fluoro-2,4-dimethyl-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-{3-[2-(1H-imidazol-4-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(3-imidazol-1-yl-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(2-methyl-3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(2-hydroxy-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(2-methyl-3-piperidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(2-hydroxy-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethoxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethoxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethoxy)-5-(3-furan-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethoxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Methyl-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(2-hydroxy-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(3-imidazol-1-yl-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(2-methyl-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-(3-furan-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(2,6-dimethyl-morpholin-4-yl)-2-methyl-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-{3-(2-(3H-imidazol-4-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido-3-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethoxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(3-phenyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-Cyclobutyl-ureido)-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(2,3-Difluoro-benzyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Allyl-ureido)-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Fluoro-2,4-dimethyl-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-[3-(2-methyl-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-{3-[3-(2,6-Dimethyl-morpholin-4-yl)-2-methyl-propyl]-ureido}-3-(2-fluoro-4,6-dimethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-[3-(2-hydroxy-3-morpholin-4-y)-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-[3-(3-imidazol-1-yl-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-{3-[2-(1H-imidazol-4-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(4-morpholin-4-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(4-morpholin-4-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-(3-morpholin-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-benzyloxy)-5-(3-morpholin-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

2-Aminomethyl-morpholine-4-carboxylic acid[4-carbamoyl-3-(2,3-dichloro-benzyloxy)-isothiazol-5-yl]-amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(2-methyl-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-{3-[3-(2,6-Dimethyl-morpholin-4-yl)-2-methyl-propyl]-ureido}-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(2-hydroxy-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(4-morpholin-4-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-[3-(2-hydroxy-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-[3-(2-methyl-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-[3-(4-morpholin-4-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(2-methyl-allyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-cyclohexylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-dimethylamino-2,2-dimethyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(2-hydroxy-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(3-imidazol-1-yl-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-furan-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1H-imidazol-4-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-3-(4-bromo-2-fluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-diethylamino-2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(2-hydroxy-3,3-dimethyl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(2,3-dihydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(4-morpholin-4-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(2-hydroxy-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-(2,3-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(2-methyl-3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-{3-[3-(2,6-dimethyl-morpholin-4-yl)-2-methyl-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(3-Cyclohexylamino-propyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[2-(1H-imidazol-4-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(2-methyl-allyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-{3-[3-(2,6-dimethyl-morpholin-4-yl)-2-methyl-propyl]-ureido}-isothiazole-4-carboxylicacid amide

5-(3-Allyl-ureido)-3-(2-fluoro-4,6-dimethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-{3-[3-(2-methyl-piperidin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(2-methyl-3-piperidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(2-methyl-3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-(3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(4-morpholin-4-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-1H-pyrrol-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(2,3-dihydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Allyl-ureido)-3-(2,3-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-Cyclohexylmethyl-ureido)-3-(2,3-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(2-piperidin-1-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(2-methyl-3-piperidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(2,6-dimethyl-morpholin-4-yl)-2-methyl-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-thiophen-2-ylmethoxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[2-(3-methyl-3H-imidazol-4-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(2-pyrrolidin-1-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(2-methyl-3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(1-Benzyl-pyrrolidin-3-yl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(1-Ethyl-pyrrolidin-2-ylmethyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(3-Dimethylamino-2,2-dimethyl-propyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(2-methyl-3-piperidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(3-methyl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-(3-morpholin-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

2-Aminomethyl-morpholine-4-carboxylic acid[4-carbamoyl-3-(2,3-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-amide;

3-(2,3-Dichloro-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(3-Cyclohexylamino-propyl)-ureido]-3-(2,3-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-iodo-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(3-imidazol-1-yl-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-(3-furan-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl)-ureido)-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Diethylamino-2-hydroxy-propyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-{3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(2-hydroxy-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-(3-methyl-ureido)-isothiazole-4-carboxylicacid amide;

5-[3-(2-Dimethylamino-ethyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Dimethylamino-propyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-(3-ethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-(3-methyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-(3-propyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(2-hydroxy-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-1H-pyrrol-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-[3-(4-morpholin-4-y-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-{3-[2-(1H-imidazol-4-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-(3-furan-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-{3-[3-(2,6-Dimethyl-morpholin-4-yl)-2-methyl-propyl]-ureido}-3-(4-ethyl-2,3-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(4-Dimethylamino-butyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-dibutylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(3-diethylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[3-(2-methyl-piperidin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(3-Dibutylamino-propyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-1H-pyrrol-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(3-Cyclohexylamino-propyl)-ureido]-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(2,3-dihydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-morpholin-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

2-Aminomethyl-morpholine-4-carboxylic acid[4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-amide;

5-(3-Allyl-ureido)-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(tetrahydro-furan-2-ylmethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;5-[3-(3-Cyclohexylamino-propyl)-ureido]-3-(4-ethyl-2,3-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-(4-ethyl-2,3-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-Allyl-ureido)-3-(4-ethyl-2,3-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Diethylamino-propyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(6-Dimethylamino-hexyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methoxy-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methoxy-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methoxy-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methoxy-benzyloxy)-5-[3-(4-morpholin-4-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-3-(2-fluoro-4-methoxy-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methoxy-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(3-Dimethylamino-propyl)-ureido]-3-(2-fluoro-4-methoxy-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Dimethylamino-butyl)-ureido]-3-(2-fluoro-4-methoxy-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methoxy-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(3-Cyclohexylamino-propyl)-ureido]-3-(2-fluoro-4-methoxy-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,5-difluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methoxy-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,5-difluoro-benzyloxy)-5-[3-(4-morpholin-4-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,5-difluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,5-difluoro-benzyloxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,5-difluoro-benzyloxy)-5-[3-(3-morpholin-4-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,5-difluoro-benzyloxy)-5-[3-(2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,5-difluoro-benzyloxy)-5-(3-furan-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,5-difluoro-benzyloxy)-5-{3-[2-(3H-imidazol-4-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,5-difluoro-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,5-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,5-difluoro-benzyloxy)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

5-[3-(2,3-Dihydroxy-propyl)-ureido]-3-(4-ethyl-2,3-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-(3-morpholin-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

2-Aminomethyl-morpholine-4-carboxylic acid[4-carbamoyl-3-(2-fluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-(3-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(3-Diethylamino-2-hydroxy-propyl)-ureido]-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(4-morpholin-4-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-(3-cyclopropylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(6-Dimethylamino-hexyl)-ureido]-3-(2-fluoro-4,6-dimethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Dimethylamino-butyl)-ureido]-3-(2-fluoro-4,6-dimethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-(3-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-[3-(3-tert-Butylamino-propyl)-ureido]-3-(2-fluoro-4,6-dimethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(6-Dimethylamino-hexyl)-ureido]-3-(2,4,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,5-difluoro-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(3-Cyclohexylamino-propyl)-ureido]-3-(4-ethyl-2,5-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Chloro-4-methyl-benzyloxy)-5-[3-(4-morpholin-4-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Chloro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Chloro-4-methyl-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Chloro-4-methyl-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Chloro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(3-imidazol-1-yl-propyl)-ureido]-3-(2,4,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Dimethylamino-butyl)-ureido]-3-(2,4,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(2-fluoro-4,6-dimethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[4-(;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(4-methyl-piperazin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-[3-(3-tert-Butylamino-propyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,4-Difluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,4-Difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,4-Difluoro-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,4-Difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-trifluoromethyl-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,4-Difluoro-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,4-Difluoro-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Dichloro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Dichloro-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Dichloro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Dichloro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Dichloro-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Dichloro-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-3-(4-chloro-2,5-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[4-(4-methyl-piperazin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-(3-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(4-Benzyl-piperazin-1-yl)-butyl]-ureido}-3-(4-chloro-2,5-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(2-Azepan-1-yl-ethyl)-ureido]-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(1-Aza-bicyclo[2.2.2]oct-4-ylmethyl)-ureido]-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-1-methyl-pyrrolidin-2-ylmethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(3-diethylamino-2-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-(3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(3-hydroxy-2-methyl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

2-Aminomethyl-morpholine-4-carboxylic acid[4-carbamoyl-3-(4-chloro-2,5-difluoro-benzyloxy)-isothiazol-5-yl]-amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-(3-morpholin-2-ylmethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-(3-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Fluoro-2,4-dimethyl-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(5-morpholin-4-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-(5-(4-methyl-piperazin-1-yl-pentyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro4-methyl-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[7-(4-methyl-piperazin-1-yl)-heptyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[6-(4-methyl-piperazin-1-yl)-hexyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{7-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-heptyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Dichloro-4-methyl-benzyloxy)-5-{3-[4-(4-methyl-piperazin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Dichloro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Dichloro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[7-(4-methyl-piperazin-1-yl)-heptyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[6-(4-methyl-piperazin-1-yl)-hexyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-(3-{7-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-heptyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[5-(4-methyl-piperazin-1-yl)-pentyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[5-(4-methyl-piperazin-1-yl)-pentyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[7-(4-methyl-piperazin-1-yl)-heptyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-(3-{7-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-heptyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[6-(4-methyl-piperazin-1-yl)-hexyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[6-(4-propyl-piperazin-1-yl)-hexyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-(3-{5-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-3-(4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{6-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-3-(4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-{3-[5-(4-methyl-piperazin-1-yl)-pentyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-{3-[7-(4-methyl-piperazin-1-yl)-heptyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-{3-[6-(4-methyl-piperazin-1-yl)-hexyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-(3-{7-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-heptyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(4-chloro-2,5-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(5-morpholin-4-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

7-{3-[4-Carbamoyl-3-(4-chloro-2,5-difluoro-benzyloxy)-isothiazol-5-yl]-ureidomethyl}-octahydro-pyrido[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(4-chloro-2,5-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(5-Isopropylamino-pentyl)-ureido]-3-(2,4,5-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(6-Dimethylamino-hexyl)-ureido]-3-(2,4,5-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Pyrrolidin-1-yl-butyl)-ureido]-3-(2,4,5-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{6-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-hexyl)ureido}-3-(2,4,5-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{7-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-heptyl}-ureido)-3-(2,4,5-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(2-Morpholin-4-yl-ethyl)-ureido]-3-(2,4,5-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}isothiazole-4-carboxylicacid amide;

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl}ureido)-3-(4-chloro-2,6-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(4-methyl-piperazin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[5-(4-methyl-piperazin-1-yl)-pentyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-(3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino)-propyl}-ureido)-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[4-(2-hydroxy-ethyl)]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide;

4-{3-[4-Carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-ureido}-butyricacid

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-3-(2-chloro-5-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Chloro-5-fluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-{(6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-[3-(3-tert-Butylamino-propyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[3-hydroxy-5-(4-methyl-piperazin-1-yl)-pentyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2-Chloro-5-fluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Chloro-5-fluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[3-hydroxy-5-(4-methyl-piperazin-1-yl)-pentyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Chloro-5-fluoro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Chloro-5-fluoro-4-methyl-benzyloxy)-5-(3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-hydroxy-5-(4-methyl-piperazin-1-yl)-pentyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-2-fluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-2-fluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-3-(5-chloro-2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(2-fluoro-4,6-dimethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-2-fluoro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-2-fluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-(6-Dimethylamino-hexyl)-ureido]-3-(2,4,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-2-fluoro-4-methyl-benzyloxy)-5-(3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-2-fluoro-4-methyl-benzyloxy)-5-{3-[4-(4-methyl-piperazin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-2-fluoro-4-methyl-benzyloxy)-5-(3-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(4-chloro-2,6-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-2-fluoro-4-methyl-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-2-fluoro-4-methyl-benzyloxy)-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide;

7-{3-[4-Carbamoyl-3-(4-chloro-2,6-difluoro-benzyloxy)-isothiazol-5-yl]-ureidomethyl}-octahydro-pyrido[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl})-ureido)-3-(4-chloro-2,6-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-3-(2,3-dichloro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-4-methyl-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-4-methyl-benzyloxy)-5-(3-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,3-dichloro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-4-methyl-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,3-Dichloro-4-methyl-benzyloxy)-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,4-Dimethyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-benzyloxy)-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-[3-(6-Dimethylamino-hexyl)-ureido]-3-(4-ethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-[3-(6-Dimethylamino-hexyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-Heptyloxy-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-Heptyloxy-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(5-Isopropylamino-pentyl)-ureido]-3-(2,4,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-3-(2,4,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(2,4,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Pyrrolidin-1-yl-butyl)-ureido]-3-(2,4,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-3-(2,4,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{5-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-3-(2,4,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{6-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-3-(2,4,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-[3-(4-tert-butylamino-3-hydroxy-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-(3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2-fluoro-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl56-ureido)-3-(2-fluoro-4,6-dimethyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-(3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4,6-dimethyl-benzyloxy)-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-[1-(4-Chloro-2,6-difluoro-phenyl)-ethoxy]-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-[1-(4-Chloro-2,6-difluoro-phenyl)-ethoxy]-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-[3-(6-Dimethylamino-hexyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(5-Isopropylamino-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{6-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-[1-(4-chloro-2,6-difluoro-phenyl)-ethoxy]-isothiazole-4-carboxylicacid amide;

5-(3-{5-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-[1-(4-Chloro-2,6-difluoro-phenyl)-ethoxy]-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-(3-{5-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-3-(4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{6-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-3-(4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(6-Dimethylamino-hexyl)-ureido]-3-(4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(6-Dimethylamino-hexyl)-ureido]-3-heptyloxy-isothiazole-4-carboxylicacid amide;

3-Heptyloxy-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(5-Chloro-2-fluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(6-Dimethylamino-hexyl)-ureido]-3-(2,3,5,6-tetrafluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{6-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-3-(2,3,5,6-tetrafluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(4-Pyrrolidin-1-yl-butyl)-ureido]-3-(2,3,5,6-tetrafluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(2,3,5,6-tetrafluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(5-Isopropylamino-pentyl)-ureido]-3-(2,3,5,6-tetrafluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[2-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[6-(4-methyl-piperazin-1-yl)-hexyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(4-piperidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-piperidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(4-piperidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(4-piperidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,6-difluoro-benzyloxy)-5-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-hexyl}-ureido)-isothiazole-4-carboxylic acid amide;

3-(4-Bromo-2,6-difluoro-benzyloxy)-5-(3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pentyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-tert-butylamino-3-hydroxy-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-isobutylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(4-tert-Butylamino-3-hydroxy-butyl)-ureido]-3-(2-fluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-morpholin-4-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(5-hydroxy-6-morpholin-4-yl-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(5-hydroxy-6-morpholin-4-yl-hexyl))-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(3-hydroxy-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(5-hydroxy-6-morpholin-4-yl-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-morpholin-4-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-[3-(5-hydroxy-6-morpholin-4-yl-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(5-hydroxy-6-isobutylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(5-hydroxy-6-piperidin-1-yl-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(6-hydroxy-7-morpholin-4-yl-heptyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-morpholin-4-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(7-dimethylamino-6-hydroxy-heptyl)-ureido]-isothiazole-4-carboxylicacid amide

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(6-hydroxy-7-piperidin-1-yl-heptyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(2-methoxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-methoxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(6-Dimethylamino-hexyl)-ureido]-3-(2,3,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[3-(4-Methyl-piperazin-1-yl)-propyl]-ureido}-3-(2,3,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,3-Difluoro-4-methyl-benzyloxy)-5-[3-(5-hydroxy-6-piperidin-1-yl-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(5-hydroxy-6-piperidin-1-yl-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Ethyl-2,3-difluoro-benzyloxy)-5-[3-(5-hydroxy-6-piperidin-1-yl-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(5-hydroxy-6-piperidin-1-yl-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(5-hydroxy-6-morpholin-4-yl-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2-fluoro-benzyloxy)-5-[3-(6-hydroxy-7-morpholin-4-ylheptyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(6-hydroxy-7-morpholin-4-yl-heptyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(6-hydroxy-7-morpholin-4-yl-heptyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(5-hydroxy-6-piperidin-1-yl-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(6-hydroxy-7-piperidin-1-yl-heptyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(7-dimethylamino-6-hydroxy-heptyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(6-hydroxy-7-piperidin-1-yl-heptyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(7-dimethylamino-6-hydroxy-heptyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(5-hydroxy-6-isobutylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(5-hydroxy-6-isobutylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2-Fluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(3-Chloro-2,6-difluoro-benzyloxy)-5-[3-(6-dimethylamino-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-piperidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(4-Pyrrolidin-1-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[3-(4-Methyl-piperazin-1-yl)-propyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-isothiazole-4-carboxylicacid amide

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[4-(3-hydroxy-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,5-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-ethyl-3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-ethyl-3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[3-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-ethyl-3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-ethyl-3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-ethyl-3-(4-piperidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-ethyl-3-(4-piperidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-Methyl-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-Ethyl-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-Cyclobutyl-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-Allyl-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-Isobutyl-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Hydroxy-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(2-Dimethylamino-ethyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Dimethylamino-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(7-Dimethylamino-6-hydroxy-heptyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Dimethylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Hydroxy-5-isopropylamino-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Isopropylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[3-(4-Methyl-piperazin-1-yl)-propyl]-ureido56-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acidamide;

5-{3-[4-(4-Methyl-piperazin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[5-(4-Methyl-piperazin-1-yl)-pentyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[6-(4-Methyl-piperazin-1-yl)-hexyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[3-Hydroxy-5-(4-methyl-piperazin-1-yl)-pentyl]-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[4-(3-Hydroxy-propyl)-piperazin-1-yl]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Pyrrolidin-1-yl-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-methyl-3-(4-piperidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-methyl-3-(4-piperidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(4-Pyrrolidin-1-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Hydroxy-5-piperidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(5-Hydroxy-6-piperidin-1-yl-hexyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(5-Hydroxy-7-piperidin-1-yl-heptyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(4-Hydroxy-5-morpholin-4-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(5-Hydroxy-6-morpholin-4-yl-hexyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(5-Hydroxy-7-morpholin-4-yl-heptyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(2-Morpholin-4-yl-ethyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Morpholin-4-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{3-[Bis-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-tert-Butylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-{3-[4-(2-Methoxymethyl-pyrrolidin-1-yl)-butyl]-ureido)3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-methyl-3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-{3-[4-(3-Hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-methyl-3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-{3-[4-(3,4-Dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(2-Hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(3-Hydroxy-piperidin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(2-Hydroxymethyl-piperidin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Cyclohexylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{-4-[Bis-(2-hydroxy-propyl)-amino]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[3-(5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-propyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Imidazol-1-yl-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(3-hydroxy-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-methyl-ureido)-isothiazole-4-carboxylicacid amide;

5-(3-Cyclopropylmethyl-ureido)-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-Cyclobutyl-ureido)-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-Allyl-ureido)-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-isobutyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(2-dimethylamino-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(7-dimethylamino-6-hydroxy-heptyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-dimethylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(4-methyl-piperazin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[5-(4-methyl-piperazin-1-yl)-pentyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[6-(4-methyl-piperazin-1-yl)-hexyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[3-hydroxy-5-(4-methyl-piperazin-1-yl)-pentyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-{3-[4-(4-Acetyl-piperazin-1-yl)-butyl]-ureido}-3-(4-chloro-2,6-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(4-Acetyl-piperazin-1-yl)-butyl]-ureido}-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-piperidin-1-yl)-butyl]-3-methyl-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-3-methyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,3,6-Trifluoro-4-methyl-benzyloxy)-5-ureido-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,6-difluoro-benzyloxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino)-butyl}-3-methyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-piperidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(5-hydroxy-6-piperidin-1-yl-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(6-hydroxy-7-piperidin-1-yl-heptyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-hydroxy-5-morpholin-4-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(5-hydroxy-6-morpholin-4-yl-hexyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(6-hydroxy-7-morpholin-4-yl-heptyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-morpholin-4-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-[3-(3-tert-Butylamino-propyl)-ureido]-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-methoxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(4-Imidazol-1-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[5-(4-methyl-piperazin-1-yl)-pentyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[3-hydroxy-5-(4-methyl-piperazin-1-yl)-pentyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-(3-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-piperidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(3-Cyclohexylamino-propyl)-ureido]-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-ureido-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-ethyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-cyclopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(3-Cyclopropylamino-propyl)-ureido]-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-(3-{3-[ethyl-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-(3-{3-[ethyl-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-(3-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-ureido)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(3-hydroxy-5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-(3-{3-[ethyl-(2-hydroxy-ethyl)-amino]-propyl}-ureido)-isothiazole-4-carboxylicacid amide;

5-{3-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Dimethylamino-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Dimethylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Hydroxy-5-isopropylamino-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Isopropylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(4-Methyl-piperazin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[4-(3-Hydroxy-propyl)-piperazin-1-yl]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Pyrrolidin-1-yl-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Hydroxy-5-piperidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-Ethyl-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-Methyl-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Bis-(2-hydroxy-propyl)-amino]-butyl}-ureido)-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[3-(4-Acetyl-piperazin-1-yl)-propyl]-ureido}-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[3-(4-Acetyl-piperazin-1-yl)-propyl]-ureido}-3-(4-chloro-2,3,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(1,3-Difluoro-naphthalen-2-ylmethoxy)-5-(3-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-isothiazole-4-carboxylicacid amide

5-{3-[3-(4-Acetyl-piperazin-1-yl)-propyl]-ureido}-3-(4-chloro-2,6-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(4-Acetyl-piperazin-1-yl)-butyl]-ureido}-3-(4-chloro-2,3,6-trifluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(3-imidazol-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(2-Amino-ethyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Amino-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(5-Amino-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(6-Amino-hexyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(7-Amino-heptyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(1,3-Difluoro-naphthalen-2-ylmethoxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(1,3-Difluoro-naphthalen-2-ylmethoxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(1,3-Difluoro-naphthalen-2-ylmethoxy)-5-{3-[3-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(1,3-Difluoro-naphthalen-2-ylmethoxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(1,3-Difluoro-naphthalen-2-ylmethoxy)-5-{3-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(3-Hydroxy-piperidin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-tert-Butylamino-propyl)-ureido-]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(3-Hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(3,4-Dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(2-Hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[4-(2-Hydroxymethyl-piperidin-1-yl)-butyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-(3-methyl-ureido)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{-3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(2-dimethylamino-ethyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-ureido)-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[3-(5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-propyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-dimethylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-5-isopropylamino-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(3-Cyclohexylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-isopropylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(3-Amino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[2-(2-Amino-ethoxy)-ethyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Pyrrolidin-1-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[3-(4-Methyl-piperazin-1-yl)-propyl]-ureido}3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(4-Amino-butyl)-ureido]-3-(4-chloro-2,6-difluoro-benzyloxy)-isothiazole-4-carboxylicacidamide;5-[3-(7-amino-heptyl)-ureido]-3-(4-chloro-2,6-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(5-Amino-pentyl)-ureido]-3-(4-chloro-2,6-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;5-[3-(4-Amino-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Azepan-1-yl-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Diethylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Methylamino-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-{3-[3-(2-Methyl-piperidin-1-yl)-propyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(pyridin-2-ylamino)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[3-(pyridin-2-ylamino)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

5-[3-(6-Amino-hexyl)-ureido]-3-(4-chloro-2,6-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(pyridin-2-ylamino)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6trifluoro-benzyloxy)-5-(3-[4-(pyridin-2-ylamino)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-difluoro-benzyloxy)-5-{3-[3-(pyridin-2-ylamino)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[3-(pyridin-2-ylamino)-propyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-cyclopropylamino-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(3-Amino-propyl)-3-methyl-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(3-Chloro-2,6-difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(3-Chloro-2,6-difluoro-4-methyl-benzyloxy)-5-[3-(3-dimethylamino-propyl)-ureido]-isothiazole-4-carboxylicacid amide;

3-(3-Chloro-2,6-difluoro-4-methyl-benzyloxy)-5-[3-(4-dimethylamino-butyl)-ureido]-isothiazole-4-carboxylicacid amide;

5-[3-(2-Amino-ethyl)-ureido]-3-(4-chloro-2,6-difluoro-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(2-Amino-ethyl)-ureido]-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(7-Amino-heptyl)-ureido]-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

5-[3-(3-Amino-propyl)-ureido]-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;

3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(pyridin-4-ylamino)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(pyridin-4-ylamino)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;

3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(pyridin-4-ylamino)-butyl]-ureido}-isothiazole-4-carboxylicacid amide.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein, X¹ is O or S; R¹ is —(CH₂)_(t)(4-5 membered heterocyclic),wherein t is an integer from 0 to 5; said heterocyclic group isoptionally fused to a C₆-C₁₀aryl group, a C₅-C₈ saturated cyclic group,or a 5-10 membered heterocyclic group; and said R¹ group, including theoptionally fused portions of said R¹ group, is optionally substituted by1 or 2 substituents independently selected from C₁-C₄ alkyl, hydroxy andhydroxymethyl; R² is H; R³ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, —(CH₂)_(t)(C₆-C₁₀ aryl), or —(CH₂)_(t)(5-10 memberedheterocyclic), wherein t is an integer from 0 to 5; said alkyl groupoptionally include 1 or 2 hetero moieties selected from O, S and —N(R⁶)—with the proviso that two O atoms, two S atoms, or an O and S atom arenot attached directly to each other; said aryl and heterocyclic R³groups are optionally fused to a C₆-C₁₀ aryl group, a C₅-C₈ saturatedcyclic group, or a 5-10 membered heterocyclic group; 1 or 2 carbon atomsin the foregoing heterocyclic moieties are optionally substituted by anoxo (═O) moiety; the —(CH₂)_(t)— moieties of the foregoing R³ groupsoptionally include a carbon-carbon double or triple bond where t is aninteger from 2 to 5, and the foregoing R³ groups are optionallysubstituted by 1 to 5 R⁴ groups; each R⁴ is independently selected fromC₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, azido, —OR⁵, —C(O)R⁵, —C(O)OR⁵,—NR⁶C(O)OR⁵, —OC(O)R⁵, —NR⁶SO₂R⁵, —SO₂NR⁵R⁶, —NR⁶C(O)R⁵, —C(O)NR⁵R⁶,—NR⁵R⁶, —S(O)_(j)R⁷ wherein j is an integer ranging from 0 to 2, —SO₃H,—NR⁵(CR⁶R⁷)_(t)OR⁶, —(CH₂)_(t)(C₆-C₁₀ aryl), —SO₂(CH₂)_(t)(C₆-C₁₀ aryl),—S(CH₂)_(t)(C₆-C₁₀ aryl), —O(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(t)(5-10membered heterocyclic), and —(CR⁶R⁷)_(m)OR⁶, wherein m is an integerfrom 1 to 5 and t is an integer from 0 to 5; said alkyl group optionallycontains 1 or 2 hetero moieties selected from O, S and —N(R⁶)— with theproviso that two O atoms, two S atoms, or an O and S atom are notattached directly to each other; said aryl and heterocyclic R⁴ groupsare optionally fused to a C₆-C₁₀ aryl group, a C₅-C₈ saturated cyclicgroup, or a 5-10 membered heterocyclic group; 1 or 2 carbon atoms in theforegoing heterocyclic moieties are optionally substituted by an oxo(═O) moiety; and the alkyl, aryl and heterocyclic moieties of theforegoing R⁴ groups are optionally substituted by 1 to 3 substituentsindependently selected from halo, cyano, nitro, trifluoromethyl,trifluoromethoxy, azido, —NR⁶SO₂R⁵, —SO₂NR⁵R⁶, —C(O)R⁵, —C(O)OR⁵,—OC(O)R⁵, —NR⁶C(O)R⁵, —C(O)NR⁵R⁶, —NR⁵R⁶, —(CR⁶R⁷)_(m)OR⁶ wherein m isan integer from 1 to 5, —OR⁵ and the substituents listed in thedefinition of R⁵; each R₅ is independently selected from H, C₁-C₁₀alkyl, —(CH₂)_(t)(C₆-C₁₀ aryl), and —(CH₂)_(t)(5-10 memberedheterocyclic), wherein t is an integer from 0 to 5; said alkyl groupoptionally includes 1 or 2 hetero moieties selected from O, S and—N(R⁶)— with the proviso that two O atoms, two S atoms, or an O and Satom are not attached directly to each other; said aryl and heterocyclicR⁵ groups are optionally fused to a C₆-C₁₀ aryl group, a C₅-C₈ saturatedcyclic group, or a 5-10 membered heterocyclic group; and the foregoingR⁵ subsituents, except H, are optionally substituted by 1 to 3substituents independently selected from halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, azido, —C(O)R⁶, —C(O)OR⁶, —CO(O)R⁶,—NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, hydroxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy;and each R⁶ and R⁷ is independently H or C₁-C₆ alkyl.
 2. A compoundaccording to claim 1 wherein R³ is —(CH₂)_(t)(C₆-C₁₀ aryl) wherein t isan integer from 1 to 3 and said R³ group is optionaly substituted by 1to 4 R⁴ groups.
 3. A compound according to claim 2 wherein R³ is benzyloptionally substituted by 1 to 4 substituents independently selectedfrom halo and C₁-C₄ alkyl.
 4. A compound according to claim 3 wherein R³is benzyl substituted by 1 to 4 substituents independently selected frommethyl, fluoro, chloro and bromo.
 5. The compound of claim 1, wherein R¹is —(CH₂)_(t)(4 membered heterocyclic).
 6. The compound of claim 1,wherein R¹ is —(CH₂)_(t)(5 membered heterocyclic).
 7. The compound ofclaim 6, wherein the 5-membered heterocyclic is selected from the groupconsisting of pyrrolidine, imidazole, furan and tetrazole.
 8. Thecompound of claim 7, wherein the 5-membered heterocyclic is pyrrolidine.9. A compound according to claim 1 selected from the group consistingof: mesylate salt of3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido}-isothiazole-4-carboxylicacid amide; hydrochloride salt of3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl)-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido-}-isothiazole-4-carboxylicacid amide;3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl]-ureido]-isothiazole-4-carboxylicacid amide;3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;5-[3-(4-Pyrrolidin-1-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;5-[3-(3-Hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylicacid amide;5-{3-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;5-[3-(3-Pyrrolidin-1-yl-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylicacid amide;3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylicacid amide;3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylicacid amide;3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide;3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide; and3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylicacid amide; and the pharmaceutically acceptable salts, prodrugs andsolvates of said compounds. 10.3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide, or a pharmaceutically acceptable salt of said compound, or aprodrug of said compound or said pharmaceutically acceptable salt ofsaid compound.
 11. The compound of claim 9, wherein said compound is thehydrochloride salt of3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide.
 12. The compound of claim 9, wherein said compound is themesylate salt of3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide.
 13. A pharmaceutical composition for the treatment of ahyperproliferative disorder in a mammal which comprises atherapeutically effective amount of a compound according to claim 1 anda pharmaceutically acceptable carrier.
 14. The pharmaceuticalcomposition of claim 13 wherein said hyperproliferative disorder is acancer selected from brain, lung, squamous cell, bladder, gastric,pancreatic, breast, head, neck, renal, kidney, ovarian, prostate,colorectal, oesophageal, gynecological and thyroid cancer.
 15. Thepharmaceutical composition of claim 13 wherein said disorder is anon-cancerous hyperproliferative disorder.
 16. The pharmaceuticalcomposition of claim 15 wherein said disorder is a benign hyperplasia ofthe skin or prostate.
 17. The pharmaceutical composition of claim 13,wherein said compound is the hydrochloride salt of3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide.
 18. The pharmaceutical composition of claim 13, wherein saidcompound is the mesylate salt of3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylicacid amide.
 19. A method of treating a hyperproliferative disorder in amammal which comprises administering to said mammal a therapeuticallyeffective amount of a compound according to claim
 1. 20. The method ofclaim 19 wherein said method is for the treatment of a cancer selectedfrom brain, squamous cell, bladder, gastric, pancreatic, breast, head,neck, oesophageal, prostate, colorectal, lung, renal, kidney, ovarian,gynecological and thyroid cancer.
 21. The method of claim 20 whereinsaid method is for the treatment of a non-cancerous hyperproliferativedisorder.
 22. The method of claim 21 wherein said method is for thetreatment of a benign hyperplasia of the skin or prostate.
 23. A methodfor the treatment of a hyperproliferative disorder in a mammal whichcomprises administering to said mammal a therapeutically effectiveamount of a compound according to claim 1 in combination with ananti-tumor agent selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,NK1 receptor antagonist, 5-HT3 receptor antagonist, COX-2 inhibitor, anEGFR inhibitor, and anti-androgens.